Hepatitis C Virus Inhibitors

ABSTRACT

The present disclosure relates to compounds, compositions and methods for the treatment of Hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Continuation application claims the benefit of U.S. Ser. No.13/672,266, filed Nov. 8, 2012, now pending, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.12/939,778 filed Nov. 4, 2010, now abandoned, which in turn is aNon-Provisional application which claims the benefit of U.S. ProvisionalApplication Ser. No. 61/378,806 filed Aug. 31, 2010, now expired andU.S. Provisional Application Ser. No. 61/260,115 filed Nov. 11, 2009,now expired, all incorporated herein by reference in their entireties.

The present disclosure is generally directed to antiviral compounds, andmore specifically directed to compounds which can inhibit the functionof the NS5A protein encoded by Hepatitis C virus (HCV), compositionscomprising such compounds, and methods for inhibiting the function ofthe NS5A protein.

HCV is a major human pathogen, infecting an estimated 170 millionpersons worldwide—roughly five times the number infected by humanimmunodeficiency virus type 1. A substantial fraction of these HCVinfected individuals develop serious progressive liver disease,including cirrhosis and hepatocellular carcinoma.

The current standard of care for HCV, which employs a combination ofpegylated-interferon and ribavirin, has a non-optimal success rate inachieving sustained viral response and causes numerous side effects.Thus, there is a clear and long-felt need to develop effective therapiesto address this undermet medical need.

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the 5′untranslated region, HCV has been classified as a separate genus in theFlaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome due to the high error rateof the encoded RNA dependent RNA polymerase which lacks a proof-readingcapability. At least six major genotypes have been characterized, andmore than 50 subtypes have been described with distribution worldwide.The clinical significance of the genetic heterogeneity of HCV hasdemonstrated a propensity for mutations to arise during monotherapytreatment, thus additional treatment options for use are desired. Thepossible modulator effect of genotypes on pathogenesis and therapyremains elusive.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to herein as NS3 protease) andmediates all the subsequent cleavages downstream of NS3, both in cis, atthe NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions by both acting as a cofactor for the NS3 protease andassisting in the membrane localization of NS3 and other viral replicasecomponents. The formation of a NS3-NS4A complex is necessary for properprotease activity resulting in increased proteolytic efficiency of thecleavage events. The NS3 protein also exhibits nucleoside triphosphataseand RNA helicase activities. NS5B (also referred to herein as HCVpolymerase) is a RNA-dependent RNA polymerase that is involved in thereplication of HCV with other HCV proteins, including NS5A, in areplicase complex.

Compounds useful for treating HCV-infected patients are desired whichselectively inhibit HCV viral replication. In particular, compoundswhich are effective to inhibit the function of the NS5A protein aredesired. The HCV NS5A protein is described, for example, in thefollowing references: Tan, S. L. et al., Virology, 284:1-12 (2001);Park, K.-J. et al., J. Biol. Chem., 30711-30718 (2003); Tellinghuisen,T. L. et al., Nature, 435:374 (2005); Love, R. A. et al., J. Virol.,83:4395 (2009); Appel, N. et al., J. Biol. Chem., 281:9833 (2006);Huang, L., J. Biol. Chem., 280:36417 (2005); Rice, C. et al., WorldPatent Application WO 2006/093867.

In its first aspect the present disclosure provides a compound ofFormula (I)

or a pharmaceutically acceptable salt thereof, wherein:

X and X′ are each independently selected from CH, CR¹, and N;

Y and Y′ are each independently selected from CH, CR², and N;

provided that no more than two of X, X′, Y, and Y′ are N;

R¹ and R² are independently selected from

each R³ is independently selected from hydrogen, cyano, and halo;

each R⁴ is independently selected from hydrogen, and alkyl, wherein thealkyl can optionally form a fused three- to five-membered ring with anadjacent carbon atom wherein said ring is optionally substituted withone or two methyl groups; or, R⁴ and the carbon to which it is attachedform an ethylene group;

each R⁵ is independently selected from hydrogen and —C(O)R⁶;

each R⁶ is independently selected from alkoxy, alkyl, arylalkoxy,arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,(NR^(c)R^(d))alkenyl, and (NR^(c)R^(d))alkyl; and

each R⁷ and R⁸ is independently selected from hydrogen and alkyl.

In a first embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

X and X′ are independently selected from CH and CR¹; and

Y, and Y′ are independently selected from CH and CR².

In a second embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

X and X′ are independently selected from CH and CR¹; and

Y and Y′ are each N.

In a third embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

Y and X′ are each N;

X is selected from CH and CR¹; and

Y′ is selected from CH and CR².

In a fourth embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

X′ is N; and

X is selected from CH and CR¹; and

Y and Y′ are independently selected from CH and CR².

In a second aspect the present disclosure provides a compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier. In a firstembodiment of the second aspect the composition further comprises atleast one additional compound having anti-HCV activity. In a secondembodiment of the second aspect at least one of the additional compoundsis an interferon or a ribavirin. In a third embodiment of the secondaspect the interferon is selected from interferon alpha 2B, pegylatedinterferon alpha, consensus interferon, interferon alpha 2A, andlymphoblastoid interferon tau.

In a fourth embodiment of the second aspect the present disclosureprovides a composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablecarrier, and at least one additional compound having anti-HCV activity,wherein at least one of the additional compounds is selected frominterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

In a fifth embodiment of the second aspect the present disclosureprovides a composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablecarrier, and at least one additional compound having anti-HCV activity,wherein at least one of the additional compounds is effective to inhibitthe function of a target selected from HCV metalloprotease, HCV serineprotease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCVassembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment ofan HCV infection.

In a third aspect the present disclosure provides a method of treatingan HCV infection in a patient, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof. In a first embodiment of thethird aspect the method further comprises administering at least oneadditional compound having anti-HCV activity prior to, after orsimultaneously with the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. In a second embodiment of the third aspect atleast one of the additional compounds is an interferon or a ribavirin.In a third embodiment of the third aspect the interferon is selectedfrom interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastoid interferon tau.

In a fourth embodiment of the third aspect the present disclosureprovides a method of treating an HCV infection in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and at least one additional compound having anti-HCV activity prior to,after or simultaneously with the compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of theadditional compounds is selected from interleukin 2, interleukin 6,interleukin 12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, Imiqimod,ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor,amantadine, and rimantadine.

In a fifth embodiment of the third aspect the present disclosureprovides a method of treating an HCV infection in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and at least one additional compound having anti-HCV activity prior to,after or simultaneously with the compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of theadditional compounds is effective to inhibit the function of a targetselected from HCV metalloprotease, HCV serine protease, HCV polymerase,HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCVNS5A protein, and IMPDH for the treatment of an HCV infection.

Other aspects of the present disclosure may include suitablecombinations of embodiments disclosed herein.

Yet other aspects and embodiments may be found in the descriptionprovided herein.

The description of the present disclosure herein should be construed incongruity with the laws and principals of chemical bonding. In someinstances it may be necessary to remove a hydrogen atom in orderaccommodate a substituent at any given location.

It should be understood that the compounds encompassed by the presentdisclosure are those that are suitably stable for use as pharmaceuticalagent.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. For example, when R¹ and R² both contain anR4 group, the two R⁴ groups may be the same or different.

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

As used in the present specification, the following terms have themeanings indicated:

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

Unless stated otherwise, all aryl, cycloalkyl, and heterocyclyl groupsof the present disclosure may be substituted as described in each oftheir respective definitions. For example, the aryl part of an arylalkylgroup may be substituted as described in the definition of the term“aryl”.

The term “alkenyl,” as used herein, refers to a straight or branchedchain group of two to six carbon atoms containing at least onecarbon-carbon double bond.

The term “alkenyloxy,” as used herein, refers to an alkenyl groupattached to the parent molecular moiety through an oxygen atom.

The term “alkenyloxycarbonyl,” as used herein, refers to an alkenyloxygroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkoxy groups.

The term “alkoxyalkylcarbonyl,” as used herein, refers to an alkoxyalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylcarbonyloxy,” as used herein, refers to an alkylcarbonylgroup attached to the parent molecular moiety through an oxygen atom.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon containing from one tosix carbon atoms. In the compounds of the present disclosure, when R⁴ isalkyl, the alkyl can optionally form a fused three-membered ring with anadjacent carbon atom to provide the structure shown below.

wherein n is selected from 1 and 2.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylsulfanyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfur atom.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfonyl group.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicfused ring system wherein one or both of the rings is a phenyl group.Bicyclic fused ring systems consist of a phenyl group fused to a four-to six-membered aromatic or non-aromatic carbocyclic ring. The arylgroups of the present disclosure can be attached to the parent molecularmoiety through any substitutable carbon atom in the group.Representative examples of aryl groups include, but are not limited to,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The arylgroups of the present disclosure are optionally substituted with one,two, three, four, or five substituents independently selected fromalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, asecond aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(x)R^(y),(NR^(x)R^(y))alkyl, oxo, and —P(O)OR₂, wherein each R is independentlyselected from hydrogen and alkyl; and wherein the alkyl part of thearylalkyl and the heterocyclylalkyl are unsubstituted and wherein thesecond aryl group, the aryl part of the arylalkyl, the aryl part of thearylcarbonyl, the heterocyclyl, and the heterocyclyl part of theheterocyclylalkyl and the heterocyclylcarbonyl are further optionallysubstituted with one, two, or three substituents independently selectedfrom alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “arylalkoxy,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkoxy group.

The term “arylalkoxycarbonyl,” as used herein, refers to an arylalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryl groups. The alkyl part of thearylalkyl is further optionally substituted with one or two additionalgroups independently selected from alkoxy, alkylcarbonyloxy, halo,haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and —NR^(c)R^(d), whereinthe heterocyclyl is further optionally substituted with one or twosubstituents independently selected from alkoxy, alkyl, unsubstitutedaryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo,haloalkoxy, haloalkyl, hydroxy, —NR^(x)R^(y), and oxo.

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclicor bicyclic hydrocarbon ring system having three to fourteen carbonatoms and zero heteroatoms. Representative examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[3.1.1]heptyl, and adamantyl. The cycloalkyl groupsof the present disclosure are optionally substituted with one, two,three, four, or five substituents independently selected from alkoxy,alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy,hydroxyalkyl, nitro, and —NR^(x)R^(y), wherein the aryl and theheterocyclyl are further optionally substituted with one, two, or threesubstituents independently selected from alkoxy, alkyl, cyano, halo,haloalkoxy, haloalkyl, hydroxy, nitro, and oxo.

The term “cycloalkyloxy,” as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “cycloalkyloxycarbonyl,” as used herein, refers to acycloalkyloxy group attached to the parent molecular moiety through acarbonyl group.

The term “cycloalkylsulfonyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “ethylene,” as used herein, refers to ═CH₂.

The term “formyl,” as used herein, refers to —CHO.

The terms “halo” and “halogen,” as used herein, refers to Cl, Br, F, orI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkoxycarbonyl,” as used herein, refers to a haloalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, three, or four halogen atoms.

The term “heterocyclyl,” as used herein, refers to a four-, five-, six-,or seven-membered ring containing one, two, three, or four heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Thefour-membered ring has zero double bonds, the five-membered ring haszero to two double bonds, and the six- and seven-membered rings havezero to three double bonds. The term “heterocyclyl” also includesbicyclic groups in which the heterocyclyl ring is fused to anothermonocyclic heterocyclyl group or a three- to seven-membered aromatic ornon-aromatic carbocyclic ring; bicyclic groups in which the heterocyclylring is substituted with a three- to seven-membered spirocyclic ring; aswell as bridged bicyclic groups such as 7-azabicyclo[2.2.1]hept-7-yl,2-azabicyclo[2.2.2]oct-2-yl, and 2-azabicyclo[2.2.2]oct-3-yl. Theheterocyclyl groups of the present disclosure can be attached to theparent molecular moiety through any carbon atom or nitrogen atom in thegroup. Examples of heterocyclyl groups include, but are not limited to,benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl,piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl,pyrrolyl, quinolinyl, tetrahydropyranyl, thiazolyl, thienyl, andthiomorpholinyl. The heterocyclyl groups of the present disclosure areoptionally substituted with one, two, three, four, or five substituentsindependently selected from alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxycarbonyl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(x)R^(y), (NR^(x)R^(y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl, thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro.

The term “heterocyclylalkoxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an alkoxy group.

The term “heterocyclylalkoxycarbonyl,” as used herein, refers to aheterocyclylalkoxy group attached to the parent molecular moiety througha carbonyl group.

The term “heterocyclylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three heterocyclyl groups. The alkyl partof the heterocyclylalkyl is further optionally substituted with one ortwo additional groups independently selected from alkoxy,alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(c)R^(d), wherein the aryl is further optionally substituted withone or two substituents independently selected from alkoxy, alkyl,unsubstituted aryl, unsubstituted arylalkoxy, unsubstitutedarylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(x)R^(y).

The term “heterocyclylalkylcarbonyl,” as used herein, refers to aheterocyclylalkyl group attached to the parent molecular moiety througha carbonyl group.

The term “heterocyclylcarbonyl,” as used herein, refers to aheterocyclyl group attached to the parent molecular moiety through acarbonyl group.

The term “heterocyclyloxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an oxygen atom.

The term “heterocyclyloxycarbonyl,” as used herein, refers to aheterocyclyloxy group attached to the parent molecular moiety through acarbonyl group.

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three hydroxy groups.

The term “hydroxyalkylcarbonyl,” as used herein, refers to ahydroxyalkyl group attached to the parent molecular moiety through acarbonyl group.

The term “nitro,” as used herein, refers to —NO₂.

The term “—NR^(c)R^(d),” as used herein, refers to two groups, R^(c) andR^(d), which are attached to the parent molecular moiety through anitrogen atom. R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, cycloalkyloxy, alkylsulfonyl, aryl, arylalkoxycarbonyl,arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl,arylsulfonyl, cycloalkyl, cycloalkyloxycarbonyl, cycloalkylsulfonyl,formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl,heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(x)R^(y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^(c)R^(d))alkenyl,” as used herein, refers to

wherein R^(c) and R^(d) are as defined herein and each R^(q) isindependently hydrogen or C₁₋₃ alkyl.

The term “(NR^(c)R^(d))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(c)R^(d) groups. The alkyl partof the (NR^(c)R^(d))alkyl is further optionally substituted with one ortwo additional groups selected from alkoxy, alkoxyalkylcarbonyl,alkoxycarbonyl, alkylsulfanyl, C₂ alkynyl, arylalkoxycarbonyl, carboxy,cyano, cycloalkyl, halo, heterocyclyl, heterocyclylcarbonyl, hydroxy,and (NR^(e)R^(f))carbonyl; wherein the heterocyclyl is furtheroptionally substituted with one, two, three, four, or five substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro.

The term “—NR^(e)R^(f),” as used herein, refers to two groups, R^(e) andR^(f), which are attached to the parent molecular moiety through anitrogen atom. R^(e) and R^(f) are independently selected from hydrogen,alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstitutedcycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstitutedheterocyclyl, unsubstituted heterocyclylalkyl, (NR^(x)R^(y))alkyl, and(NR^(x)R^(y))carbonyl.

The term “(NR^(e)R^(f))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(e)R^(f) groups.

The term “(NR^(e)R^(f))alkylcarbonyl,” as used herein, refers to an(NR^(e)R^(f))alkyl group attached to the parent molecular moiety througha carbonyl group.

The term “(NR^(e)R^(f))carbonyl,” as used herein, refers to an—NR^(e)R^(f) group attached to the parent molecular moiety through acarbonyl group.

The term “(NR^(e)R^(f))sulfonyl,” as used herein, refers to an—NR^(e)R^(f) group attached to the parent molecular moiety through asulfonyl group.

The term “—NR^(x)R^(y),” as used herein, refers to two groups, R^(x) andR^(y), which are attached to the parent molecular moiety through anitrogen atom. R^(x) and R^(y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(x′)R^(y′))carbonyl, wherein R^(x′)and R^(y′) are independently selected from hydrogen and alkyl.

The term “(NR^(x)R^(y))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(x)R^(y) groups.

The term “(NR^(x)R^(y))carbonyl,” as used herein, refers to an—NR^(x)R^(y) group attached to the parent molecular moiety through acarbonyl group.

The term “—NR^(x)R^(y),” as used herein, refers to two groups, R^(x) andR^(y), which are attached to the parent molecular moiety through anitrogen atom. R^(x) and R^(y) are independently selected from hydrogenand alkyl.

The term “(NR^(x′)R^(y′))carbonyl,” as used herein, refers to an—NR^(x′)R^(y′) group attached to the parent molecular moiety through acarbonyl group.

The term “oxo,” as used herein, refers to ═O.

The term “sulfonyl,” as used herein, refers to —SO₂—.

Asymmetric centers exist in the compounds of the present disclosure.These centers are designated by the symbols “R” or “S”, depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the disclosure encompasses all stereochemicalisomeric forms, or mixtures thereof, which possess the ability toinhibit NS5A. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of stereoisomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, or direct separation of stereoisomers onchiral chromatographic columns. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

Certain compounds of the present disclosure may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present disclosure includes eachconformational isomer of these compounds and mixtures thereof

The compounds of the present disclosure also exist as tautomers;therefore the present disclosure also encompasses all tautomeric forms.

The term “compounds of the present disclosure”, and equivalentexpressions, are meant to embrace compounds of Formula (I), andpharmaceutically acceptable stereoisomers, diastereomers, and saltsthereof. Similarly, references to intermediates are meant to embracetheir salts where the context so permits.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds may have a variety of potential uses,for example as standards and reagents in determining biologicalactivity. In the case of stable isotopes, such compounds may have thepotential to favorably modify biological, pharmacological, orpharmacokinetic properties.

The compounds of the present disclosure can exist as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent disclosure which are water or oil-soluble or dispersible, whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use. The salts can be prepared during the final isolationand purification of the compounds or separately by reacting a suitablenitrogen atom with a suitable acid. Representative acid addition saltsinclude acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate;digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Examples of acids which can beemployed to form pharmaceutically acceptable addition salts includeinorganic acids such as hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,and N,N′-dibenzylethylenediamine. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of Formula (I), as well as pharmaceuticallyacceptable salts thereof, may be administered as the raw chemical, it ispossible to present the active ingredient as a pharmaceuticalcomposition. Accordingly, the disclosure further provides pharmaceuticalcompositions, which include therapeutically effective amounts ofcompounds of Formula (I) or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The term “therapeutically effective amount,” as used herein,refers to the total amount of each active component that is sufficientto show a meaningful patient benefit, e.g., a sustained reduction inviral load. When applied to an individual active ingredient,administered alone, the term refers to that ingredient alone. Whenapplied to a combination, the term refers to combined amounts of theactive ingredients that result in the therapeutic effect, whetheradministered in combination, serially, or simultaneously. The compoundsof Formula (I) and pharmaceutically acceptable salts thereof, are asdescribed above. The carrier(s), diluent(s), or excipient(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Inaccordance with another aspect of the present disclosure there is alsoprovided a process for the preparation of a pharmaceutical formulationincluding admixing a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, with one or more pharmaceutically acceptablecarriers, diluents, or excipients. The term “pharmaceuticallyacceptable,” as used herein, refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofpatients without excessive toxicity, irritation, allergic response, orother problem or complication commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Dosage levels of between about 0.01 and about 250 milligram per kilogram(“mg/kg”) body weight per day, preferably between about 0.05 and about100 mg/kg body weight per day of the compounds of the present disclosureare typical in a monotherapy for the prevention and treatment of HCVmediated disease. Typically, the pharmaceutical compositions of thisdisclosure will be administered from about 1 to about 5 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that maybe combined with the carrier materials to produce a single dosage formwill vary depending on the condition being treated, the severity of thecondition, the time of administration, the route of administration, therate of excretion of the compound employed, the duration of treatment,and the age, gender, weight, and condition of the patient. Preferredunit dosage formulations are those containing a daily dose or sub-dose,as herein above recited, or an appropriate fraction thereof, of anactive ingredient. Generally, treatment is initiated with small dosagessubstantially less than the optimum dose of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. In general, the compound is mostdesirably administered at a concentration level that will generallyafford antivirally effective results without causing any harmful ordeleterious side effects.

When the compositions of this disclosure comprise a combination of acompound of the present disclosure and one or more additionaltherapeutic or prophylactic agent, both the compound and the additionalagent are usually present at dosage levels of between about 10 to 150%,and more preferably between about 10 and 80% of the dosage normallyadministered in a monotherapy regimen.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intracutaneous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional, intravenous, or intradermalinjections or infusions) route. Such formulations may be prepared by anymethod known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s) or excipient(s).Oral administration or administration by injection are preferred.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate, or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate, or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, and the like. Lubricantsused in these dosage forms include sodium oleate, sodium chloride, andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets areformulated, for example, by preparing a powder mixture, granulating orslugging, adding a lubricant and disintegrant, and pressing intotablets. A powder mixture is prepared by mixing the compound, suitablecomminuted, with a diluent or base as described above, and optionally,with a binder such as carboxymethylcellulose, an aliginate, gelating, orpolyvinyl pyrrolidone, a solution retardant such as paraffin, aresorption accelerator such as a quaternary salt and/or and absorptionagent such as betonite, kaolin, or dicalcium phosphate. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present disclosure can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of Formula (I), and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research,3(6):318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and soutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The term “patient” includes both human and other mammals.

The term “treating” refers to: (i) preventing a disease, disorder orcondition from occurring in a patient that may be predisposed to thedisease, disorder, and/or condition but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, disorder, or condition, i.e.,arresting its development; and (iii) relieving the disease, disorder, orcondition, i.e., causing regression of the disease, disorder, and/orcondition.

The compounds of the present disclosure can also be administered with acyclosporin, for example, cyclosporin A. Cyclosporin A has been shown tobe active against HCV in clinical trials (Hepatology, 38:1282 (2003);Biochem. Biophys. Res. Commun., 313:42 (2004); J. Gastroenterol., 38:567(2003)).

Table 1 below lists some illustrative examples of compounds that can beadministered with the compounds of this disclosure. The compounds of thedisclosure can be administered with other anti-HCV activity compounds incombination therapy, either jointly or separately, or by combining thecompounds into a composition.

TABLE 1 Type of Inhibitor or Brand Name Physiological Class TargetSource Company NIM811 Cyclophilin Novartis Debio-025 inhibitorsDebiopharm Zadaxin Immunomodulator Sciclone Suvus Methylene blueBioenvision Actilon (CPG10101) TLR9 agonist Coley Batabulin (T67)Anticancer β-Tubulin inhibitor Tularik Inc., South San Francisco, CAISIS 14803 Antiviral Antisense ISIS Pharmaceuticals Inc, Carlsbad, CA/Elan Pharmaceuticals Inc., New York, NY Summetrel Antiviral AntiviralEndo Pharmaceuticals Holdings Inc., Chadds Ford, PA GS-9132 (ACH-806)Antiviral HCV inhibitor Achillion/Gilead Pyrazolopyrimidine AntiviralHCV inhibitors Arrow Therapeutics compounds and salts Ltd. From WO2005/047288 26 May 2005 Levovirin Antiviral IMPDH inhibitor RibapharmInc., Costa Mesa, CA Merimepodib Antiviral IMPDH inhibitor Vertex(VX-497) Pharmaceuticals Inc., Cambridge, MA XTL-6865 (XTL-002)Antiviral Monoclonal XTL antibody Biopharmaceuticals Ltd., Rehovot,Israel Telaprevir Antiviral NS3 serine Vertex (VX-950, LY-570310)protease inhibitor Pharmaceuticals Inc., Cambridge, MA/Eli Lilly and Co.Inc., Indianapolis, IN HCV-796 Antiviral NS5B replicase Wyeth/Viropharmainhibitor NM-283 Antiviral NS5B replicase Idenix/Novartis inhibitorGL-59728 Antiviral NS5B replicase Gene Labs/Novartis inhibitor GL-60667Antiviral NS5B replicase Gene Labs/Novartis inhibitor 2′C MeA AntiviralNS5B replicase Gilead inhibitor PSI 6130 Antiviral NS5B replicase Rocheinhibitor R1626 Antiviral NS5B replicase Roche inhibitor 2′C Methyladenosine Antiviral NS5B replicase Merck inhibitor JTK-003 AntiviralRdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Levovirin AntiviralRibavirin ICN Pharmaceuticals, Costa Mesa, CA Ribavirin AntiviralRibavirin Schering-Plough Corporation, Kenilworth, NJ ViramidineAntiviral Ribavirin prodrug Ribapharm Inc., Costa Mesa, CA HeptazymeAntiviral Ribozyme Ribozyme Pharmaceuticals Inc., Boulder, CO BILN-2061Antiviral Serine protease Boehringer Ingelheim inhibitor Pharma KG,Ingelheim, Germany SCH 503034 Antiviral Serine protease Schering-Ploughinhibitor Zadazim Immune modulator Immune modulator SciClonePharmaceuticals Inc., San Mateo, CA Ceplene Immunomodulator Immunemodulator Maxim Pharmaceuticals Inc., San Diego, CA CELLCEPT ®Immunosuppressant HCV IgG immuno- F. Hoffmann-La suppressant Roche LTD,Basel, Switzerland Civacir Immunosuppressant HCV IgG immuno- Nabisuppressant Biopharmaceuticals Inc., Boca Raton, FL Albuferon - αInterferon Albumin IFN-α2b Human Genome Sciences Inc., Rockville, MDInfergen A Interferon IFN alfacon-1 InterMune Pharmaceuticals Inc.,Brisbane, CA Omega IFN Interferon IFN-ω Intarcia Therapeutics IFN-β andEMZ701 Interferon IFN-β and Transition EMZ701 Therapeutics Inc.,Ontario, Canada REBIF ® Interferon IFN-β1a Serono, Geneva, SwitzerlandRoferon A Interferon IFN-α2a F. Hoffmann-La Roche LTD., Basel,Switzerland Intron A Interferon IFN-α2b Schering-Plough Corporation,Kenilworth, NJ Intron A and Zadaxin Interferon IFN-α2b/α1- RegeneRxthymosin Biopharma. Inc., Bethesda, MD/ SciClone Pharmaceuticals Inc,San Mateo, CA Rebetron Interferon IFN-α2b/ribavirin Schering-PloughCorporation, Kenilworth, NJ Actimmune Interferon INF-γ InterMune Inc.,Brisbane, CA Interferon-β Interferon Interferon-β-1a Serono MultiferonInterferon Long lasting IFN Viragen/Valentis Wellferon InterferonLymphoblastoid GlaxoSmithKline plc, IFN-αn1 Uxbridge, UK OmniferonInterferon natural IFN-α Viragen Inc., Plantation, FL Pegasys InterferonPEGylated IFN- F. Hoffmann-La α2a Roche LTD, Basel, Switzerland Pegasysand Ceplene Interferon PEGylated IFN- Maxim α2a/immune PharmaceuticalsInc., modulator San Diego, CA Pegasys and Ribavirin Interferon PEGylatedIFN- F. Hoffmann-La α2a/ribavirin Roche LTD, Basel, SwitzerlandPEG-Intron Interferon PEGylated IFN- Schering-Plough α2b Corporation,Kenilworth, NJ PEG-Intron/Ribavirin Interferon PEGylated IFN-Schering-Plough α2b/ribavirin Corporation, Kenilworth, NJ IP-501 Liverprotection Antifibrotic Indevus Pharmaceuticals Inc., Lexington, MAIDN-6556 Liver protection Caspase inhibitor Idun Pharmaceuticals Inc.,San Diego, CA ITMN-191 (R-7227) Antiviral Serine protease InterMuneinhibitor Pharmaceuticals Inc., Brisbane, CA GL-59728 Antiviral NS5Breplicase Genelabs inhibitor ANA-971 Antiviral TLR-7 agonist AnadysBoceprevir Antiviral Serine protease Schering-Plough inhibitor TMS-435Antiviral Serine protease Tibotec BVBA, inhibitor Mechelen, BelgiumBI-201335 Antiviral Serine protease Boehringer Ingelheim inhibitorPharma KG, Ingelheim, Germany MK-7009 Antiviral Serine protease Merckinhibitor PF-00868554 Antiviral Replicase inhibitor Pfizer ANA598Antiviral Non-Nucleoside Anadys NS5B polymerase Pharmaceuticals, Inc.,inhibitor San Diego, CA, USA IDX375 Antiviral Non-Nucleoside Idenixreplicase inhibitor Pharmaceuticals, Cambridge, MA, USA BILB 1941Antiviral NS5B polymerase Boehringer Ingelheim inhibitor Canada Ltd R&D,Laval, QC, Canada PSI-7851 Antiviral Nucleoside Pharmasset, polymerasePrinceton, NJ, USA inhibitor VCH-759 Antiviral NS5B polymerase Vir °ChemPharma inhibitor VCH-916 Antiviral NS5B polymerase Vir °Chem Pharmainhibitor GS-9190 Antiviral NS5B polymerase Gilead inhibitorPeg-interferon lamda Antiviral Interferon ZymoGenetics/ Bristol-MyersSquibb

The compounds of the present disclosure may also be used as laboratoryreagents. Compounds may be instrumental in providing research tools fordesigning of viral replication assays, validation of animal assaysystems and structural biology studies to further enhance knowledge ofthe HCV disease mechanisms. Further, the compounds of the presentdisclosure are useful in establishing or determining the binding site ofother antiviral compounds, for example, by competitive inhibition.

The compounds of this disclosure may also be used to treat or preventviral contamination of materials and therefore reduce the risk of viralinfection of laboratory or medical personnel or patients who come incontact with such materials, e.g., blood, tissue, surgical instrumentsand garments, laboratory instruments and garments, and blood collectionor transfusion apparatuses and materials.

This disclosure is intended to encompass compounds having Formula (I)when prepared by synthetic processes or by metabolic processes includingthose occurring in the human or animal body (in vivo) or processesoccurring in vitro.

The abbreviations used in the present application, includingparticularly in the illustrative examples which follow, are well-knownto those skilled in the art. Some of the abbreviations used are asfollows: Ph for phenyl; DME for 1,2-dimethoxyethane; TFA fortrifluoroacetic acid; DCM for dichloromethane; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; DMF for N,N-dimethylformamide; iPr₂EtN, DIEA, orDIPEA for diisopropylethylamine; h, hr, or hrs for hrs; MeOD for CD₃OD;MeOH for methanol; min or mins for minutes; EtOH for ethanol; Et forethyl; DMSO for dimethylsulfoxide; rt or RT or Rt for room temperatureor retention time (context will dictate); EDCI for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Boc, boc,or BOC for tert-butoxycarbonyl; EtOAc or EtOAc for ethyl acetate; THFfor tetrahydrofuran; TBDPS for t-butyldimethylsilyl; DMAP for4-dimethylaminopyridine; TBAF for tetrabutylammonium fluoride; OAc foracetate; AcOH for acetic acid; SEMCl for 2-(trimethylsilyl)ethoxymethylchloride; d for days; TEA or Et₃N for triethylamine; ACN or MeCN foracetonitrile; NCS for N-chlorosuccinimide; NBS for N-bromosuccinimide;Et₂O for diethyl ether; DCE for 1,2-dichloroethane; d for days; and DEAfor diethylamine.

The present disclosure will now be described in connection with certainembodiments which are not intended to limit its scope. On the contrary,the present disclosure covers all alternatives, modifications, andequivalents as can be included within the scope of the claims. Thus, thefollowing examples, which include specific embodiments, will illustrateone practice of the present disclosure, it being understood that theexamples are for the purposes of illustration of certain embodiments andare presented to provide what is believed to be the most useful andreadily understood description of its procedures and conceptual aspects.

Starting materials can be obtained from commercial sources or preparedby well-established literature methods known to those of ordinary skillin the art.

Synthesis of Common Caps Compound Analysis Conditions

Purity assessment and low resolution mass analysis were conducted on aShimadzu LC system coupled with Waters MICROMASS® ZQ MS system. Itshould be noted that retention times may vary slightly between machines.Additional LC conditions applicable to the current section, unless notedotherwise.

Cond.-MS-W1 Column=XTERRA® 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-MS-W2 Column=XTERRA® 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-MS-W5 Column=XTERRA® 3.0×50 mm S7 Start % B=0 Final % B=30

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-D1 Column=XTERRA® C18 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-D2 Column=PHENOMENEX® Luna 4.6×50 mm S10 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-M3 Column=XTERRA® C18 3.0×50 mm S7 Start % B=0 Final % B=40

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Condition I Column=PHENOMENEX® Luna 3.0×50 mm S10 Start % B=0 Final %B=100

Gradient time=2 minStop time=3 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Condition II Column=PHENOMENEX® Luna 4.6×50 mm S10 Start % B=0 Final %B=100

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Condition III Column=XTERRA® C18 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

(R)-2-(Dimethylamino)-2-phenylacetic acid

A suspension of 10% Pd/C (2.0 g) in methanol (10 mL) was added to amixture of (R)-2-phenylglycine (10 g, 66.2 mmol), formaldehyde (33 mL of37% wt. in water), 1N HCl (30 mL) and methanol (30 mL), and exposed toH₂ (60 psi) for 3 hours. The reaction mixture was filtered throughdiatomaceous earth (CELITE®), and the filtrate was concentrated invacuo. The resulting crude material was recrystallized from isopropanolto provide the HCl salt of Cap-1 as a white needle (4.0 g). Opticalrotation: −117.1° [c=9.95 mg/mL in H₂O; λ=589 nm]. ¹H NMR (DMSO-d₆,δ=2.5 ppm, 500 MHz): δ 7.43-7.34 (m, 5H), 4.14 (s, 1H), 2.43 (s, 6H); LC(Condition I): RT=0.25; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.10.found 180.17; HRMS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.1025. found180.1017.

(R)-2-(Diethylamino)-2-phenylacetic acid

NaBH₃CN (6.22 g, 94 mmol) was added in portions over a few minutes to acooled (ice/water) mixture of (R)-2-Phenylglycine (6.02 g, 39.8 mmol)and methanol (100 mL), and stirred for 5 minutes. Acetaldehyde (10 mL)was added dropwise over 10 minutes and stirring was continued at thesame cooled temperature for 45 minutes and at ambient temperature for˜6.5 hours. The reaction mixture was cooled back with ice-water bath,treated with water (3 mL) and then quenched with a dropwise addition ofconcentrated HCl over ˜45 minutes until the pH of the mixture was˜1.5-2.0. The cooling bath was removed and the stirring was continuedwhile adding concentrated HCl in order to maintain the pH of the mixturearound 1.5-2.0. The reaction mixture was stirred overnight, filtered toremove the white suspension, and the filtrate was concentrated in vacuo.The crude material was recrystallized from ethanol to afford the HClsalt of Cap-2 as a shining white solid in two crops (crop-1: 4.16 g;crop-2: 2.19 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 10.44 (1.00, brs, 1H), 7.66 (m, 2H), 7.51 (m, 3H), 5.30 (s, 1H), 3.15 (br m, 2H), 2.98(br m, 2H), 1.20 (app br s, 6H). Crop-1: [α]²⁵−102.21° (c=0.357, H₂O);crop-2: [α]²⁵−99.7° (c=0.357, H₂O). LC (Condition I): RT=0.43 min;LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₈NO₂: 208.13. found 208.26.

Acetaldehyde (5.0 mL, 89.1 mmol) and a suspension of 10% Pd/C (720 mg)in methanol/H₂O (4 mL/1 mL) was sequentially added to a cooled (˜15° C.)mixture of (R)-2-phenylglycine (3.096 g, 20.48 mmol), 1N HCl (30 mL) andmethanol (40 mL). The cooling bath was removed and the reaction mixturewas stirred under a balloon of H₂ for 17 hours. An additionalacetaldehyde (10 mL, 178.2 mmol) was added and stirring continued underH₂ atmosphere for 24 hours [Note: the supply of H₂ was replenished asneeded throughout the reaction]. The reaction mixture was filteredthrough diatomaceous earth (CELITE®), and the filtrate was concentratedin vacuo. The resulting crude material was recrystallized fromisopropanol to provide the HCl salt of (R)-2-(ethylamino)-2-phenylaceticacid as a shining white solid (2.846 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400MHz): δ 14.15 (br s, 1H), 9.55 (br s, 2H), 7.55-7.48 (m, 5H), 2.88 (brm, 1H), 2.73 (br m, 1H), 1.20 (app t, J=7.2, 3H). LC (Condition I):RT=0.39 min; >95% homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺C₁₀H₁₄NO₂: 180.10. found 180.18.

A suspension of 10% Pd/C (536 mg) in methanol/H₂O (3 mL/1 mL) was addedto a mixture of (R)-2-(ethylamino)-2-phenylacetic acid/HCl (1.492 g,6.918 mmol), formaldehyde (20 mL of 37% wt. in water), 1N HCl (20 mL)and methanol (23 mL). The reaction mixture was stirred under a balloonof H₂ for ˜72 hours, where the H₂ supply was replenished as needed. Thereaction mixture was filtered through diatomaceous earth (CELITE®) andthe filtrate was concentrated in vacuo. The resulting crude material wasrecrystallized from isopropanol (50 mL) to provide the HCl salt of Cap-3as a white solid (985 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 10.48(br s, 1H), 7.59-7.51 (m, 5H), 5.26 (s, 1H), 3.08 (app br s, 2H), 2.65(br s, 3H), 1.24 (br m, 3H). LC (Condition I): RT=0.39 min; >95%homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.12.found 194.18; HRMS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.1180. found194.1181.

(R)-2-(Methoxycarbonylamino)-2-phenylacetic acid

ClCO₂Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water)THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl(9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol)over 6 min, and stirred at similar temperature for 5.5 hours. Thevolatile component was removed in vacuo, and the residue was partitionedbetween water (100 mL) and ethyl acetate (200 mL). The organic layer waswashed with 1N HCl (25 mL) and saturated NaHCO₃ solution (30 mL), dried(MgSO₄), filtered, and concentrated in vacuo. The resultant colorlessoil was triturated from hexanes, filtered and washed with hexanes (100mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)-2-phenylacetateas a white solid (7.7 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.98 (d,J=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J=8, 1H), 3.56 (s, 3H), 1.33 (s,9H). LC (Condition I): RT=1.53 min; ˜90% homogeneity index; LC-MS: Anal.Calcd. for [M+Na]⁺ C₁₄H₁₉NNaO₄: 288.12. found 288.15.

TFA (16 mL) was added dropwise to a cooled (ice/water) CH₂Cl₂ (160 mL)solution of the above product over 7 minutes, and the cooling bath wasremoved and the reaction mixture was stirred for 20 hours. Since thedeprotection was still not complete, an additional TFA (1.0 mL) wasadded and stirring continued for an additional 2 hours. The volatilecomponent was removed in vacuo, and the resulting oil residue wastreated with diethyl ether (15 mL) and hexanes (12 mL) to provide aprecipitate. The precipitate was filtered and washed with diethylether/hexanes (˜1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 asa fluffy white solid (5.57 g). Optical rotation: −176.9° [c=3.7 mg/mL inH₂O; λ=589 nm]. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.84 (br s,1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55(s, 3H). LC (Condition I): RT=1.01 min; >95% homogeneity index; LC-MS:Anal. Calcd. for [M+H]⁺ C₁₀H₁₂NO₄ 210.08. found 210.17; HRMS: Anal.Calcd. for [M+H]⁺ C₁₀H₁₂NO₄ 210.0766. found 210.0756.

A mixture of (R)-2-phenylglycine (1.0 g, 6.62 mmol), 1,4-dibromobutane(1.57 g, 7.27 mmol) and Na₂CO₃ (2.10 g, 19.8 mmol) in ethanol (40 mL)was heated at 100° C. for 21 hours. The reaction mixture was cooled toambient temperature and filtered, and the filtrate was concentrated invacuo. The residue was dissolved in ethanol and acidified with 1N HCl topH 3-4, and the volatile component was removed in vacuo. The resultingcrude material was purified by a reverse phase HPLC (water/methanol/TFA)to provide the TFA salt of Cap-5 as a semi-viscous white foam (1.0 g).¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 10.68 (br s, 1H), 7.51 (m, 5H), 5.23(s, 1H), 3.34 (app br s, 2H), 3.05 (app br s, 2H), 1.95 (app br s, 4H);RT=0.30 minutes (Condition I); >98% homogeneity index; LC-MS: Anal.Calcd. for [M+H]⁺ C₁₂H₁₆NO₂: 206.12. found 206.25.

The TFA salt of Cap-6 was synthesized from (R)-2-phenylglycine and1-bromo-2-(2-bromoethoxyl)ethane by using the method of preparation ofCap-5. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.20 (br s, 1H), 7.50 (m,5H), 4.92 (s, 1H), 3.78 (app br s, 4H), 3.08 (app br s, 2H), 2.81 (appbr s, 2H); RT=0.32 minutes (Condition I); >98%; LC-MS: Anal. Calcd. for[M+H]⁺ C₁₂H₁₆NO₃: 222.11. found 222.20; HRMS: Anal. Calcd. for [M+H]⁺C₁₂H₁₆NO₃: 222.1130. found 222.1121.

A CH₂Cl₂ (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4mmol) was added dropwise to a cooled (−5° C.) CH₂Cl₂ (200 mL) solutionof (S)-benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol),triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g,4.13 mmol), while maintaining the temperature between −5° C. and 0° C.The reaction was stirred at 0° C. for 9 hours, and then stored in afreezer (−25° C.) for 14 hours. It was allowed to thaw to ambienttemperature and washed with water (200 mL), 1N HCl (100 mL) and brine(100 mL), dried (MgSO₄), filtered, and concentrated in vacuo to providebenzyl 2-phenyl-2-(tosyloxy)acetate as a viscous oil which solidifiedupon standing (16.5 g). The chiral integrity of the product was notchecked and that product was used for the next step without furtherpurification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 7.78 (d, J=8.6, 2H),7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H),5.10 (d, J=12.5, 1H), 2.39 (s, 3H). RT=3.00 (Condition III); >90%homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₂₂H₂₀NaO₅S: 419.09.found 419.04.

A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g,15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) andN,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for7 hours. The reaction was allowed to cool to ambient temperature and thevolatile component was removed in vacuo. The residue was partitionedbetween ethylacetate and water, and the organic layer was washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting crude material was purified by flash chromatography (silicagel, ethyl acetate) to provide benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscousoil (4.56 g). Chiral HPLC analysis (CHIRALCEL® OD-H) indicated that thesample is a mixture of stereoisomers in a 38.2 to 58.7 ratio. Theseparation of the stereoisomers were effected as follow: the product wasdissolved in 120 mL of ethanol/heptane (1:1) and injected (5mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at220 nm. Stereoisomer-1 (1.474 g) and stereoisomer-2 (2.2149 g) wereretrieved as viscous oil. ¹H NMR (CDCl₃, δ=7.26, 500 MHz) 7.44-7.40 (m,2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08(d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H).RT=2.10 (Condition III); >98% homogeneity index; LC-MS: Anal. Calcd. for[M+H]⁺ C₂₀H₂₅N₂O₂: 325.19. found 325.20.

A methanol (10 mL) solution of either stereoisomer of benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate (1.0 g, 3.1 mmol) was addedto a suspension of 10% Pd/C (120 mg) in methanol (5.0 mL). The reactionmixture was exposed to a balloon of hydrogen, under a carefulmonitoring, for <50 minutes. Immediately after the completion of thereaction, the catalyst was filtered through diatomaceous earth (CELITE®)and the filtrate was concentrated in vacuo to provide Cap-7,contaminated with phenylacetic acid as a tan foam (867.6 mg; mass isabove the theoretical yield). The product was used for the next stepwithout further purification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ7.44-7.37 (m, 2H), 7.37-7.24 (m, 3H), 3.92 (s, 1H), 2.63-2.48 (app. brs, 2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT=0.31 (Condition II); >90%homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.14.found 235.15; HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.1447. found235.1440.

The synthesis of Cap-8 and Cap-9 was conducted according to thesynthesis of Cap-7 by using appropriate amines for the SN₂ displacementstep (i.e., 4-hydroxypiperidine for Cap-8 and (S)-3-fluoropyrrolidinefor Cap-9) and modified conditions for the separation of the respectivestereoisomeric intermediates, as described below.

The stereoisomeric separation of the intermediate benzyl2-(4-hydroxypiperidin-1-yl)-2-phenyl acetate was effected by employingthe following conditions: the compound (500 mg) was dissolved inethanol/heptane (5 mL/45 mL). The resulting solution was injected (5mL/injection) on a chiral HPLC column (Chiracel OJ, 2 cm ID×25 cm L, 10μm) eluting with 80:20 heptane/ethanol at 10 mL/min, monitored at 220nm, to provide 186.3 mg of stereoisomer-1 and 209.1 mg of stereoisomer-2as light-yellow viscous oils. These benzyl ester was hydrogenolysedaccording to the preparation of Cap-7 to provide Cap-8: ¹H NMR (DMSO-d₆,δ=2.5, 500 MHz) 7.40 (d, J=7, 2H), 7.28-7.20 (m, 3H), 3.78 (s 1H), 3.46(m, 1H), 2.93 (m, 1H), 2.62 (m, 1H), 2.20 (m, 2H), 1.70 (m, 2H), 1.42(m, 2H). RT=0.28 (Condition II); >98% homogeneity index; LC-MS: Anal.Calcd. for [M+H]⁺ C₁₃H₁₈NO₃: 236.13. found 236.07; HRMS: Calcd. for[M+H]⁺ C₁₃H₁₈NO₃: 236.1287. found 236.1283.

The diastereomeric separation of the intermediate benzyl2-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetate was effected byemploying the following conditions: the ester (220 mg) was separated ona chiral HPLC column (Chiracel OJ-H, 0.46 cm ID×25 cm L, 5 μm) elutingwith 95% CO₂/5% methanol with 0.1% TFA, at 10 bar pressure, 70 mL/minflow rate, and a temperature of 35° C. The HPLC elute for the respectivestereoisomers was concentrated, and the residue was dissolved in CH₂Cl₂(20 mL) and washed with an aqueous medium (10 mL water+1 mL saturatedNaHCO₃ solution). The organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo to provide 92.5 mg of fraction-1 and 59.6 mg offraction-2. These benzyl esters were hydrogenolysed according to thepreparation of Cap-7 to prepare Cap-9a and Cap-9b. Cap-9a(diastereomer-1; the sample is a TFA salt as a result of purification ona reverse phase HPLC using H₂O/methanol/TFA solvent): ¹H NMR (DMSO-d₆,δ=2.5, 400 MHz) 7.55-7.48 (m, 5H), 5.38 (d of m, J=53.7, 1H), 5.09 (brs, 1H), 3.84-2.82 (br m, 4H), 2.31-2.09 (m, 2H). RT=0.42 (ConditionI); >95% homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₅FNO₂:224.11. found 224.14; Cap-9b (diastereomer-2): ¹H NMR (DMSO-d₆, δ=2.5,400 MHz) 7.43-7.21 (m, 5H), 5.19 (d of m, J=55.9, 1H), 3.97 (s, 1H),2.95-2.43 (m, 4H), 2.19-1.78 (m, 2H). RT=0.44 (Condition I); LC-MS:Anal. Calcd. for [M+H]⁺ C₁₂H₁₅FNO₂: 224.11. found 224.14.

To a solution of D-proline (2.0 g, 17 mmol) and formaldehyde (2.0 mL of37% wt. in H₂O) in methanol (15 mL) was added a suspension of 10% Pd/C(500 mg) in methanol (5 mL). The mixture was stirred under a balloon ofhydrogen for 23 hours. The reaction mixture was filtered throughdiatomaceous earth (CELITE®) and concentrated in vacuo to provide Cap-10as an off-white solid (2.15 g). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) 3.42(m, 1H), 3.37 (dd, J=9.4, 6.1, 1H), 2.85-2.78 (m, 1H), 2.66 (s, 3H),2.21-2.13 (m, 1H), 1.93-1.84 (m, 2H), 1.75-1.66 (m, 1H). RT=0.28(Condition II); >98% homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺C₆H₁₂NO₂: 130.09. found 129.96.

A mixture of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (0.50 g, 3.8mmol), formaldehyde (0.5 mL of 37% wt. in H₂O), 12 N HCl (0.25 mL) and10% Pd/C (50 mg) in methanol (20 mL) was stirred under a balloon ofhydrogen for 19 hours. The reaction mixture was filtered throughdiatomaceous earth (CELITE®) and the filtrate was concentrated in vacuo.The residue was recrystallized from isopropanol to provide the HCl saltof Cap-11 as a white solid (337.7 mg). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz)5.39 (d m, J=53.7, 1H), 4.30 (m, 1H), 3.90 (ddd, J=31.5, 13.5, 4.5, 1H),3.33 (dd, J=25.6, 13.4, 1H), 2.85 (s, 3H), 2.60-2.51 (m, 1H), 2.39-2.26(m, 1H). RT=0.28 (Condition II); >98% homogeneity index; LC-MS: Anal.Calcd. for [M+H]⁺ C₆H₁₁FNO₂: 148.08. found 148.06.

(S)-2-(Methoxycarbonylamino)propanoic acid

L-Alanine (2.0 g, 22.5 mmol) was dissolved in 10% aqueous sodiumcarbonate solution (50 mL), and a THF (50 mL) solution of methylchloroformate (4.0 mL) was added to it. The reaction mixture was stirredunder ambient conditions for 4.5 hours and concentrated in vacuo. Theresulting white solid was dissolved in water and acidified with 1N HClto a pH˜2-3. The resulting solutions was extracted with ethyl acetate(3×100 mL), and the combined organic phase was dried (Na₂SO₄), filtered,and concentrated in vacuo to provide a colorless oil (2.58 g). 500 mg ofthis material was purified by a reverse phase HPLC (H₂O/methanol/TFA) toprovide 150 mg of Cap-12 as a colorless oil. ¹H NMR (DMSO-d₆, δ=2.5, 500MHz) 7.44 (d, J=7.3, 0.8H), 7.10 (br s, 0.2H), 3.97 (m, 1H), 3.53 (s,3H), 1.25 (d, J=7.3, 3H).

A mixture of L-alanine (2.5 g, 28 mmol), formaldehyde (8.4 g, 37 wt. %),1N HCl (30 mL) and 10% Pd/C (500 mg) in methanol (30 mL) was stirredunder a hydrogen atmosphere (50 psi) for 5 hours. The reaction mixturewas filtered through diatomaceous earth (CELITE®) and the filtrate wasconcentrated in vacuo to provide the HCl salt of Cap-13 as an oil whichsolidified upon standing under vacuum (4.4 g; the mass is abovetheoretical yield). The product was used without further purification.¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.1 (br s, 1H), 4.06 (q, J=7.4, 1H),2.76 (s, 6H), 1.46 (d, J=7.3, 3H).

(R)-2-Phenyl-2-(piperidin-1-yl)acetic acid

Step 1: A mixture of (R)-(−)-D-phenylglycine tert-butyl ester (3.00 g,12.3 mmol), NaBH₃CN (0.773 g, 12.3 mmol), KOH (0.690 g, 12.3 mmol) andacetic acid (0.352 mL, 6.15 mmol) were stirred in methanol at 0° C. Tothis mixture was added glutaric dialdehyde (2.23 mL, 12.3 mmol) dropwiseover 5 minutes. The reaction mixture was stirred as it was allowed towarm to ambient temperature and stirring was continued at the sametemperature for 16 hours. The solvent was subsequently removed and theresidue was partitioned with 10% aqueous NaOH and ethyl acetate. Theorganic phase was separated, dried (MgSO₄), filtered and concentrated todryness to provide a clear oil. This material was purified byreverse-phase preparative HPLC (Primesphere C-18, 30×100 mm;CH₃CN—H₂O-0.1% TFA) to give the intermediate ester (2.70 g, 56%) as aclear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.44 (m, 3H), 7.40-7.37 (m,2H), 3.87 (d, J=10.9 Hz, 1H), 3.59 (d, J=10.9 Hz, 1H), 2.99 (t, J=11.2Hz, 1H), 2.59 (t, J=11.4 Hz, 1H), 2.07-2.02 (m, 2H), 1.82 (d, J=1.82 Hz,3H), 1.40 (s, 9H). LC-MS: Anal. Calcd. for C₁₇H₂₅NO₂: 275. found: 276(M+H)⁺.

Step 2: To a stirred solution of the intermediate ester (1.12 g, 2.88mmol) in dichloromethane (10 mL) was added TFA (3 mL). The reactionmixture was stirred at ambient temperature for 4 hours and then it wasconcentrated to dryness to give a light yellow oil. The oil was purifiedusing reverse-phase preparative HPLC (Primesphere C-18, 30×100 mm;CH₃CN—H₂O-0.1% TFA). The appropriate fractions were combined andconcentrated to dryness in vacuo. The residue was then dissolved in aminimum amount of methanol and applied to applied to MCX LP extractioncartridges (2×6 g). The cartridges were rinsed with methanol (40 mL) andthen the desired compound was eluted using 2M ammonia in methanol (50mL). Product-containing fractions were combined and concentrated and theresidue was taken up in water. Lyophilization of this solution providedthe title compound (0.492 g, 78%) as a light yellow solid. ¹H NMR(DMSO-d₆) δ 7.50 (s, 5H), 5.13 (s, 1H), 3.09 (br s, 2H), 2.92-2.89 (m,2H), 1.74 (m, 4H), 1.48 (br s, 2H). LC-MS: Anal. Calcd. for C₁₃H₁₇NO₂:219. found: 220 (M+H)⁺.

Step 1: (S)-1-Phenylethyl 2-bromo-2-phenylacetate. To a mixture ofα-bromophenylacetic acid (10.75 g, 0.050 mol), (S)-(−)-1-phenylethanol(7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane(100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. Theresulting solution was stirred at room temperature under Ar for 18 hoursand then it was diluted with ethyl acetate, washed (H₂O×2, brine), dried(Na₂SO₄), filtered, and concentrated to give a pale yellow oil. Flashchromatography (SiO₂/hexane-ethyl acetate, 4:1) of this oil provided thetitle compound (11.64 g, 73%) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 7.53-7.17 (m, 10H), 5.95 (q, J=6.6 Hz, 0.5H), 5.94 (q, J=6.6 Hz,0.5H), 5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, J=6.6 Hz, 1.5H), 1.51(d, J=6.6 Hz, 1.5H).

Step 2: (S)-1-Phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate. To a solutionof (S)-1-phenylethyl 2-bromo-2-phenylacetate (0.464 g, 1.45 mmol) in THF(8 mL) was added triethylamine (0.61 mL, 4.35 mmol), followed bytetrabutylammonium iodide (0.215 g, 0.58 mmol). The reaction mixture wasstirred at room temperature for 5 minutes and then a solution of4-methyl-4-hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2 mL) wasadded. The mixture was stirred for 1 hour at room temperature and thenit was heated at 55-60° C. (oil bath temperature) for 4 hours. Thecooled reaction mixture was then diluted with ethyl acetate (30 mL),washed (H₂O×2, brine), dried (MgSO₄), filtered and concentrated. Theresidue was purified by silica gel chromatography (0-60% ethylacetate-hexane) to provide first the (S,R)-isomer of the title compound(0.306 g, 60%) as a white solid and then the corresponding (S,S)-isomer(0.120 g, 23%), also as a white solid. (S,R)-isomer: ¹H NMR (CD₃OD) δ7.51-7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J=6.6 Hz, 1H), 4.05 (s,1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d,J=6.6 Hz, 3H), 1.18 (s, 3H). LC-MS: Anal. Calcd. for C₂₂H₂₇NO₃: 353.found: 354 (M+H)⁺. (S,S)-isomer: ¹H NMR (CD₃OD) δ 7.41-7.30 (m, 5H),7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6 Hz, 1H), 4.06 (s,1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6, 3.3 Hz, 1H), 2.44-2.31 (m, 2H),1.75-1.65 (m, 1H), 1.65-1.54 (m, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.20 (s,3H). LC-MS: Anal. Calcd. for C₂₂H₂₇NO₃: 353. found: 354 (M+H)⁺.

Step 3: (R)-2-(4-Hydroxy-4-methylpiperidin-1-yl)-2-phenylacetic acid. Toa solution of (S)-1-phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate (0.185 g, 0.52mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL)and the mixture was stirred at room temperature for 2 hours. Thevolatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a palebluish solid (0.128 g, 98%). LC-MS: Anal. Calcd. for C₁₄H₁₉NO₃: 249.found: 250 (M+H)⁺.

Cap-16

Step 1: (S)-1-Phenylethyl 2-(2-fluorophenyl)acetate. A mixture of2-fluorophenylacetic acid (5.45 g, 35.4 mmol), (S)-1-phenylethanol (5.62g, 46.0 mmol), EDCI (8.82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) inCH₂Cl₂ (100 mL) was stirred at room temperature for 12 hours. Thesolvent was then concentrated and the residue partitioned with H₂O-ethylacetate. The phases were separated and the aqueous layer back-extractedwith ethyl acetate (2×). The combined organic phases were washed (H₂O,brine), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (BIOTAGE®/0-20% ethylacetate-hexane) to provide the title compound as a colorless oil (8.38g, 92%). ¹H NMR (400 MHz, CD₃OD) δ 7.32-7.23 (m, 7H), 7.10-7.04 (m, 2),5.85 (q, J=6.5 Hz, 1H), 3.71 (s, 2H), 1.48 (d, J=6.5 Hz, 3H).

Step 2: (R)—((S)-1-Phenylethyl)2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate. To a solution of(S)-1-phenylethyl 2-(2-fluorophenyl)acetate (5.00 g, 19.4 mmol) in THF(1200 mL) at 0° C. was added DBU (6.19 g, 40.7 mmol) and the solutionwas allowed to warm to room temperature while stirring for 30 minutes.The solution was then cooled to −78° C. and a solution of CBr₄ (13.5 g,40.7 mmol) in THF (100 mL) was added and the mixture was allowed to warmto −10° C. and stirred at this temperature for 2 hours. The reactionmixture was quenched with saturated aq. NH₄Cl and the layers wereseparated. The aqueous layer was back-extracted with ethyl acetate (2×)and the combined organic phases were washed (H₂O, brine), dried(Na₂SO₄), filtered, and concentrated in vacuo. To the residue was addedpiperidine (5.73 mL, 58.1 mmol) and the solution was stirred at roomtemperature for 24 hours. The volatiles were then concentrated in vacuoand the residue was purified by silica gel chromatography(BIOTAGE®/0-30% diethyl ether-hexane) to provide a pure mixture ofdiastereomers (2:1 ratio by ¹H NMR) as a yellow oil (2.07 g, 31%), alongwith unreacted starting material (2.53 g, 51%). Further chromatographyof the diastereomeric mixture (BIOTAGE®/0-10% diethyl ether-toluene)provided the title compound as a colorless oil (0.737 g, 11%). ¹H NMR(400 MHz, CD₃OD) δ 7.52 (ddd, J=9.4, 7.6, 1.8 Hz, 1H), 7.33-7.40 (m, 1),7.23-7.23 (m, 4H), 7.02-7.23 (m, 4H), 5.86 (q, J=6.6 Hz, 1H), 4.45 (s,1H), 2.39-2.45 (m, 4H), 1.52-1.58 (m, 4H), 1.40-1.42 (m, 1H), 1.38 (d,J=6.6 Hz, 3H). LC-MS: Anal. Calcd. for C₂₁H₂₄FNO₂: 341. found: 342(M+H)⁺.

Step 3: (R)-2-(2-Fluorophenyl)-2-(piperidin-1-yl)acetic acid. A mixtureof (R)—((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate(0.737 g, 2.16 mmol) and 20% Pd(OH)₂/C (0.070 g) in ethanol (30 mL) washydrogenated at room temperature and atmospheric pressure (H₂ balloon)for 2 hours. The solution was then purged with Ar, filtered throughdiatomaceous earth (CELITE®), and concentrated in vacuo. This providedthe title compound as a colorless solid (0.503 g, 98%). ¹H NMR (400 MHz,CD₃OD) δ 7.65 (ddd, J=9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H),7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H).LC-MS: Anal. Calcd. for C₁₃H₁₆FNO₂: 237. found: 238 (M+H)⁺.

Step 1: (S)-1-Phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate. To a solutionof (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70 mmol) in THF(25 mL) was added triethylamine (1.31 mL, 9.42 mmol), followed bytetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture wasstirred at room temperature for 5 minutes and then a solution of4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) wasadded. The mixture was stirred for 16 hours and then it was diluted withethyl acetate (100 mL), washed (H₂O×2, brine), dried (MgSO₄), filteredand concentrated. The residue was purified on a silica gel column (0-60%ethyl acetate-hexane) to provide an approximately 2:1 mixture ofdiastereomers, as judged by ¹H NMR. Separation of these isomers wasperformed using supercritical fluid chromatography (CHIRALCEL® OJ-H,30×250 mm; 20% ethanol in CO₂ at 35° C.), to give first the (R)-isomerof the title compound (0.534 g, 27%) as a yellow oil and then thecorresponding (S)-isomer (0.271 g, 14%), also as a yellow oil.(S,R)-isomer: ¹H NMR (400 MHz, CD₃OD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m,10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72(m, 1H), 2.64 (dt, J=11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt,J=11.1, 2.5 Hz, 1H), 2.20 (dt, J=12.1, 4.6 Hz, 1H), 2.10 (dt, J=12.1,4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J=6.5 Hz, 3H). LC-MS: Anal.Calcd. for C₂₇H₂₉NO₃: 415. found: 416 (M+H)⁺; (S,S)-isomer: H¹NMR (400MHz, CD₃OD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H),7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s,1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5 Hz, 1H), 2.57-2.52 (m,1H), 2.42 (dt, J=11.1, 2.5 Hz, 1H), 2.25 (dt, J=12.1, 4.6 Hz, 1H), 2.12(dt, J=12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H), 1.64 (dd,J=13.6, 3.0 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). LC-MS: Anal. Calcd. forC₂₇H₂₉NO₃: 415. found: 416 (M+H)⁺.

The following esters were prepared in similar fashion:

Intermediate-17a

Diastereomer 1: ¹H NMR (500 MHz, DMSO- d₆) δ ppm 1.36 (d, J = 6.41 Hz,3H) 2.23-2.51 (m, 4H) 3.35 (s, 4H) 4.25 (s, 1H) 5.05 (s, 2H) 5.82 (d, J= 6.71 Hz, 1H) 7.15-7.52 (m, 15H). LC-MS: Anal. Calcd. for: C₂₈H₃₀N₂O₄458.22; found: 459.44 (M + H)⁺. Diastereomer 2: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.45 (d, J = 6.71 Hz, 3H) 2.27-2.44 (m, 4H) 3.39 (s, 4H) 4.23(s, 1H) 5.06 (s, 2H) 5.83 (d, J = 6.71 Hz, 1H) 7.12 (dd, J = 6.41, 3.05Hz, 2H) 7.19-7.27 (m, 3H) 7.27-7.44 (m, 10H). LC-MS: Anal. Calcd. for:C₂₈H₃₀N₂O₄ 458.22; found: 459.44 (M + H)⁺. Intermediate-17b

Diastereomer 1: RT ₌ 11.76 minutes (Condition II); LC-MS: Anal. Calcd.for: C₂₀H₂₂N₂O₃ 338.16; found: 339.39 (M + H)⁺. Diastereomer 2: RT =10.05 minutes (Condition II). LC-MS: Anal. Calcd. for: C₂₀H₂₂N₂O₃338.16; found: 339.39 (M + H)⁺. Intermediate-17c

Diastereomer 1: T_(R =) 4.55 minutes (Condition I); LC-MS: Anal. Calcd.for: C₂₁H₂₆N₂O₂ 338.20; found: 339.45 (M + H)⁺. Diastereomer 2: T_(R =)6.00 minutes (Condition I). LC-MS: Anal. Calcd. for: C₂₁H₂₆N₂O₂ 338.20;found: 339.45 (M + H)⁺. Intermediate-17d

Diastereomer 1: RT ₌ 7.19 minutes (Condition I); LC-MS: Anal. Calcd.for: C₂₇H₂₉NO₂ 399.22; found: 400.48 (M + H)⁺. Diastereomer 2: RT = 9.76minutes (Condition I); LC-MS: Anal. Calcd. for: C₂₇H₂₉NO₂ 399.22; found:400.48 (M + H)⁺.Chiral SFC Conditions for determining retention time:

Condition I Column: CHIRALPAK® AD-H Column, 4.62×50 mm, 5 μm

Solvents: 90% CO₂-10% methanol with 0.1% DEA

Temp: 35° C. Pressure: 150 bar

Flow rate: 2.0 mL/min.UV monitored at 220 nmInjection: 1.0 mg/3 mL methanol

Condition II Column: CHIRALCEL® OD-H Column, 4.62×50 mm, 5 μm

Solvents: 90% CO₂-10% methanol with 0.1% DEA

Temp: 35° C. Pressure: 150 bar

Flow rate: 2.0 mL/min.UV monitored at 220 nmInjection: 1.0 mg/mL methanol

Cap-17, Step 2: (R)-2-(4-Hydroxy-4-phenylpiperidin-1-yl)-2-phenylaceticacid. To a solution of (S)-1-phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate (0.350 g, 0.84mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL)and the mixture was stirred at room temperature for 2 hours. Thevolatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a whitesolid (0.230 g, 88%). LC-MS: Anal. Calcd. for C₁₉H₂₁NO₃: 311.15. found:312 (M+H)⁺.

The following carboxylic acids were prepared in optically pure form in asimilar fashion:

Cap-17a

RT ₌ 2.21 (Condition II); ¹H NMR (500 MHz, DMSO- d₆) δ ppm 2.20-2.35 (m,2H) 2.34-2.47 (m, 2H) 3.37 (s, 4H) 3.71 (s, 1H) 5.06 (s, 2H) 7.06-7.53(m, 10H). LC- MS: Anal. Calcd. for: C₂₀H₂₂N₂O₄ 354.16; found: 355.38(M + H)⁺. Cap-17b

RT ₌ 0.27 (Condition III); LC-MS: Anal. Calcd. for: C₁₂H₁₄N₂O₃ 234.10;found: 235.22 (M + H)⁺. Cap-17c

RT ₌ 0.48 (Condition II); LC-MS: Anal. Calcd. for: C₁₃H₁₈N₂O₂ 234.14;found: 235.31 (M + H)⁺. Cap-17d

RT ₌ 2.21 (Condition I); LC-MS: Anal. Calcd. for: C₁₉H₂₁NO₂ 295.16;found: 296.33 (M + H)⁺.LC-MS Conditions for determining retention time:

Condition I Column: PHENOMENEX® Luna 4.6×50 mm S10 Start % B=0 Final %B=100 Gradient Time=4 min

Flow Rate=4 mL/min

Wavelength=220

Solvent A=10% methanol-90% H₂O-0.1% TFASolvent B=90% methanol-10% H₂O-0.1% TFA

Condition II Column: Waters-Sunfire 4.6×50 mm S5 Start % B=0 Final %B=100 Gradient Time=2 min

Flow Rate=4 mL/min

Wavelength=220

Solvent A=10% methanol-90% H₂O-0.1% TFASolvent B=90% methanol-10% H₂O-0.1% TFA

Condition III Column: PHENOMENEX® 10μ 3.0×50 mm Start % B=0 Final %B=100 Gradient Time=2 min

Flow Rate=4 mL/min

Wavelength=220

Solvent A=10% methanol-90% H₂O-0.1% TFASolvent B=90% methanol-10% H₂O-0.1% TFA

Step 1: (R,S)-Ethyl 2-(4-pyridyl)-2-bromoacetate. To a solution of ethyl4-pyridylacetate (1.00 g, 6.05 mmol) in dry THF (150 mL) at 0° C. underargon was added DBU (0.99 mL, 6.66 mmol). The reaction mixture wasallowed to warm to room temperature over 30 minutes and then it wascooled to −78° C. To this mixture was added CBr₄ (2.21 g, 6.66 mmol) andstirring was continued at −78° C. for 2 hours. The reaction mixture wasthen quenched with sat. aq. NH₄Cl and the phases were separated. Theorganic phase was washed (brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The resulting yellow oil was immediately purifiedby flash chromatography (SiO₂/hexane-ethyl acetate, 1:1) to provide thetitle compound (1.40 g, 95%) as a somewhat unstable yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (dd, J=4.6, 1.8 Hz, 2H), 7.45 (dd, J=4.6, 1.8Hz, 2H), 5.24 (s, 1H), 4.21-4.29 (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LC-MS:Anal. Calcd. for C₉H₁₀BrNO₂: 242, 244. found: 243, 245 (M+H)⁺.

Step 2: (R,S)-Ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate. To asolution of (R,S)-ethyl 2-(4-pyridyl)-2-bromoacetate (1.40 g, 8.48 mmol)in DMF (10 mL) at room temperature was added dimethylamine (2M in THF,8.5 mL, 17.0 mmol). After completion of the reaction (as judged by thinlayer chromatography) the volatiles were removed in vacuo and theresidue was purified by flash chromatography (BIOTAGE®, 40+M SiO₂column; 50%-100% ethyl acetate-hexane) to provide the title compound(0.539 g, 31%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d,J=6.0 Hz, 2H), 7.36 (d, J=6.0 Hz, 2H), 4.17 (m, 2H), 3.92 (s, 1H), 2.27(s, 6H), 1.22 (t, J=7.0 Hz). LC-MS: Anal. Calcd. for C₁₁H₁₆N₂O₂: 208.found: 209 (M+H)⁺.

Step 3: (R,S)-2-(4-Pyridyl)-2-(N,N-dimethylamino)acetic acid. To asolution of (R,S)-ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate(0.200 g, 0.960 mmol) in a mixture of THF-methanol-H₂O (1:1:1, 6 mL) wasadded powdered LiOH (0.120 g, 4.99 mmol) at room temperature. Thesolution was stirred for 3 hours and then it was acidified to pH 6 using1N HCl. The aqueous phase was washed with ethyl acetate and then it waslyophilized to give the dihydrochloride of the title compound as ayellow solid (containing LiCl). The product was used as such insubsequent steps. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=5.7 Hz, 2H),7.34 (d, J=5.7 Hz, 2H), 3.56 (s, 1H), 2.21 (s, 6H).

The following examples were prepared in similar fashion using the methoddescribed above:

Cap-19

LC-MS: Anal. Calcd. for C₉H₁₂N₂O₂: 180; found: 181 (M + H)⁺. Cap-20

LC-MS: no ionization. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 4.3 Hz,1H), 7.84 (app t, J = 5.3 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37 (appt, J = 5.3 Hz, 1H), 4.35 (s, 1H), 2.60 (s, 6H). Cap-21

LC-MS: Anal. Calcd. for C₉H₁₁ClN₂O₂: 214, 216; found: 215, 217 (M + H)⁺.Cap-22

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-23

LC-MS: Anal. Calcd. for C₁₄H₁₅NO₂: 229; found: 230 (M + H)⁺. Cap-24

LC-MS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248 (M + H)⁺. Cap-25

LC-MS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248 (M + H)⁺. Cap-26

LC-MS: Anal. Calcd. for C₁₀H₁₂FNO₂: 197; found: 198 (M + H)⁺. Cap-27

LC-MS: Anal. Calcd. for C₁₀H₁₂FNO₂: 247; found: 248 (M + H)⁺. Cap-28

LC-MS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-29

LC-MS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-30

LC-MS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-31

LC-MS: Anal. Calcd. for C₈H₁₂N₂O₂S: 200; found: 201 (M + H)⁺. Cap-32

LC-MS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186 (M + H)⁺. Cap-33

LC-MS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186 (M + H)⁺. Cap-34

LC-MS: Anal. Calcd. for C₁₁H₁₂N₂O₃: 220; found: 221 (M + H)⁺. Cap-35

LC-MS: Anal. Calcd. for C₁₂H₁₃NO₂S: 235; found: 236 (M + H)⁺. Cap-36

LC-MS: Anal. Calcd. for C₁₂H₁₄N₂O₂S: 250; found: 251 (M + H)⁺.

Step 1: (R,S)-Ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)-acetate. Amixture of ethyl N,N-dimethylaminoacetate (0.462 g, 3.54 mmol), K₃PO₄(1.90 g, 8.95 mmol), Pd(t-Bu₃P)₂ (0.090 g, 0.176 mmol), 3-bromoquinolineand toluene (10 mL) was degassed with a stream of Ar bubbles for 15minutes. The reaction mixture was then heated at 100° C. for 12 hours,after which it was cooled to room temperature and poured into H₂O. Themixture was extracted with ethyl acetate (2×) and the combined organicphases were washed (H₂O, brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified first by reverse-phasepreparative HPLC (Primesphere C-18, 30×100 mm; CH₃CN—H₂O-5 mM NH₄OAc)and then by flash chromatography (SiO₂/hexane-ethyl acetate, 1:1) toprovide the title compound (0.128 g, 17%) as an orange oil. ¹H NMR (400MHz, CDCl₃) δ 8.90 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.03-8.01(m, 2H), 7.77 (ddd, J=8.3, 6.8, 1.5 Hz, 1H), 7.62 (ddd, J=8.3, 6.8, 1.5Hz, 1H), 4.35 (s, 1H), 4.13 (m, 2H), 2.22 (s, 6H), 1.15 (t, J=7.0 Hz,3H). LC-MS: Anal. Calcd. for C₁₅H₁₈N₂O₂: 258. found: 259 (M+H)⁺.

Step 2: (R,S) 2-(Quinolin-3-yl)-2-(N,N-dimethylamino)acetic acid. Amixture of (R,S)-ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)acetate(0.122 g, 0.472 mmol) and 6M HCl (3 mL) was heated at 100° C. for 12hours. The solvent was removed in vacuo to provide the dihydrochlorideof the title compound (0.169 g, >100%) as a light yellow foam. Theunpurified material was used in subsequent steps without furtherpurification. LC-MS: Anal. Calcd. for C₁₃H₁₄N₂O₂: 230. found: 231(M+H)⁺.

Step 1: (R)—((S)-1-Phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate and (S)—((S)-1-Phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate. To a mixture of(RS)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid (2.60 g, 13.19mmol), DMAP (0.209 g, 1.71 mmol) and (S)-1-phenylethanol (2.09 g, 17.15mmol) in CH₂Cl₂ (40 mL) was added EDCI (3.29 g, 17.15 mmol) and themixture was allowed to stir at room temperature for 12 hours. Thesolvent was then removed in vacuo and the residue partitioned with ethylacetate-H₂O. The layers were separated, the aqueous layer wasback-extracted with ethyl acetate (2×) and the combined organic phaseswere washed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified by silica gel chromatography(BIOTAGE®/0-50% diethyl ether-hexane). The resulting pure diastereomericmixture was then separated by reverse-phase preparative HPLC(Primesphere C-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give first(S)-1-phenethyl (R)-2-(dimethylamino)-2-(2-fluorophenyl)acetate (0.501g, 13%) and then (S)-1-phenethyl(S)-2-(dimethylamino)-2-(2-fluorophenyl)-acetate (0.727 g. 18%), both astheir TFA salts. (S,R)-isomer: ¹H NMR (400 MHz, CD₃OD) δ 7.65-7.70 (m,1H), 7.55-7.60 (ddd, J=9.4, 8.1, 1.5 Hz, 1H), 7.36-7.41 (m, 2H),7.28-7.34 (m, 5H), 6.04 (q, J=6.5 Hz, 1H), 5.60 (s, 1H), 2.84 (s, 6H),1.43 (d, J=6.5 Hz, 3H). LC-MS: Anal. Calcd. for C₁₈H₂₀FNO₂: 301. found:302 (M+H)⁺; (S,S)-isomer: ¹H NMR (400 MHz, CD₃OD) δ 7.58-7.63 (m, 1H),7.18-7.31 (m, 6H), 7.00 (dd, J=8.5, 1.5 Hz, 2H), 6.02 (q, J=6.5 Hz, 1H),5.60 (s, 1H), 2.88 (s, 6H), 1.54 (d, J=6.5 Hz, 3H). LC-MS: Anal. Calcd.for C₁₈H₂₀FNO₂: 301. found: 302 (M+H)⁺.

Step 2: (R)-2-(Dimethylamino)-2-(2-fluorophenyl)acetic acid. A mixtureof (R)—((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetateTFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)₂/C (0.125 g) in ethanol (30mL) was hydrogenated at room temperature and atmospheric pressure (H₂balloon) for 4 hours. The solution was then purged with Ar, filteredthrough diatomaceous earth (CELITE®), and concentrated in vacuo. Thisgave the title compound as a colorless solid (0.503 g, 98%). ¹H NMR (400MHz, CD₃OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86(s, 6H). LC-MS: Anal. Calcd. for C₁₀H₁₂FNO₂: 197. found: 198 (M+H)⁺.

The S-isomer could be obtained from (S)—((S)-1-phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt in similar fashion.

A mixture of (R)-(2-chlorophenyl)glycine (0.300 g, 1.62 mmol),formaldehyde (35% aqueous solution, 0.80 mL, 3.23 mmol) and 20%Pd(OH)₂/C (0.050 g) was hydrogenated at room temperature and atmosphericpressure (H₂ balloon) for 4 hours. The solution was then purged with Ar,filtered through diatomaceous earth (CELITE®) and concentrated in vacuo.The residue was purified by reverse-phase preparative HPLC (PrimesphereC-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give the TFA salt of the titlecompound (R)-2-(dimethylamino)-2-(2-chlorophenyl)acetic acid as acolorless oil (0.290 g, 55%). ¹H NMR (400 MHz, CD₃OD) δ 7.59-7.65 (m,2H), 7.45-7.53 (m, 2H), 5.40 (s, 1H), 2.87 (s, 6H). LC-MS: Anal. Calcd.for C₁₀H₁₂ClNO₂: 213. found: 214 (M+H)⁺.

To an ice-cold solution of (R)-(2-chlorophenyl)glycine (1.00 g, 5.38mmol) and NaOH (0.862 g, 21.6 mmol) in H₂O (5.5 mL) was added methylchloroformate (1.00 mL, 13.5 mmol) dropwise. The mixture was allowed tostir at 0° C. for 1 hour and then it was acidified by the addition ofconc. HCl (2.5 mL). The mixture was extracted with ethyl acetate (2×)and the combined organic phase was washed (H₂O, brine), dried (Na₂SO₄),filtered, and concentrated in vacuo to give the title compound(R)-2-(methoxycarbonylamino)-2-(2-chlorophenyl)acetic acid as ayellow-orange foam (1.31 g, 96%). ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.43(m, 2H), 7.29-7.31 (m, 2H), 5.69 (s, 1H), 3.65 (s, 3H). LC-MS: Anal.Calcd. for C₁₀H₁₀ClNO₄: 243. found: 244 (M+H)⁺.

To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and thesolution was stirred at room temperature for 3 hours. The reactionmixture was then diluted with ethyl acetate and extracted with H₂O (2×).The aqueous phase was lyophilized and the residue was purified by silicagel chromatography (BIOTAGE®/0-10% methanol-CH₂Cl₂) to give the titlecompound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid(2.22 g, 87%). ¹H NMR (400 MHz, CD₃OD) δ 7.37-7.44 (m, 3H), 7.29-7.33(m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H).LC-MS: Anal. Calcd. for C₁₃H₁₇NO₃: 235. found: 236 (M+H)⁺.

The following examples were similarly prepared using the methoddescribed for Cap-41:

Cap-42

LC-MS: Anal. Calcd. for C₁₄H₁₉NO₂: 233; found: 234 (M + H)⁺. Cap-43

LC-MS: Anal. Calcd. for C₁₃H₁₇NO₂: 219; found: 220 (M + H)⁺. Cap-44

LC-MS: Anal. Calcd. for C₁₁H₁₅NO₂: 193; found: 194 (M + H)⁺. Cap-45

LC-MS: Anal. Calcd. for C₁₄H₂₀N₂O₂: 248; found: 249 (M + H)⁺.

HMDS (1.85 mL, 8.77 mmol) was added to a suspension of(R)-2-amino-2-phenylacetic acid p-toluenesulfonate (2.83 g, 8.77 mmol)in CH₂Cl₂ (10 mL) and the mixture was stirred at room temperature for 30minutes. Methyl isocyanate (0.5 g, 8.77 mmol) was added in one portionstirring continued for 30 minutes. The reaction was quenched by additionof H₂O (5 mL) and the resulting precipitate was filtered, washed withH₂O and n-hexanes, and dried under vacuum.(R)-2-(3-methylureido)-2-phenylacetic acid (1.5 g; 82%). was recoveredas a white solid and it was used without further purification. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.54 (d, J=4.88 Hz, 3H) 5.17 (d, J=7.93 Hz, 1H)5.95 (q, J=4.48 Hz, 1H) 6.66 (d, J=7.93 Hz, 1H) 7.26-7.38 (m, 5H) 12.67(s, 1H). LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₃ 208.08 found 209.121 (M+H)⁺;HPLC PHENOMENEX® C-18 3.0×46 mm, 0 to 100% B over 2 minutes, 1 minutehold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=1.38 min, 90% homogeneity index.

The desired product was prepared according to the method described forCap-45a. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.17 Hz, 3H)2.94-3.05 (m, 2H) 5.17 (d, J=7.93 Hz, 1H) 6.05 (t, J=5.19 Hz, 1H) 6.60(d, J=7.63 Hz, 1H) 7.26-7.38 (m, 5H) 12.68 (s, 1H). LC-MS: Anal. Calcd.for C₁₁H₁₄N₂O₃ 222.10 found 223.15 (M+H)⁺. HPLC XTERRA® C-18 3.0×506 mm,0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10%methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2% H₃PO₄, RT=0.87min, 90% homogeneity index.

Step 1: (R)-tert-Butyl 2-(3,3-dimethylureido)-2-phenylacetate. To astirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10mmol) and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was addeddimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10minutes. After stirring at room temperature for 3 hours, the reactionwas concentrated under reduced pressure and the resulting residue wasdissolved in ethyl acetate. The organic layer was washed with H₂O, 1Naq. HCl and brine, dried (MgSO₄), filtered and concentrated underreduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetatewas obtained as a white solid (0.86 g; 75%) and used without furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 2.82 (s, 6H)5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H).LC-MS: Anal. Calcd. for C₁₅H₂₂N₂O₃ 278.16 found 279.23 (M+H)⁺; HPLCPHENOMENEX® LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minutehold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=2.26 min, 97% homogeneity index.

Step 2: (R)-2-(3,3-Dimethylureido)-2-phenylacetic acid. To a stirredsolution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86g, 3.10 mmol) in CH₂Cl₂ (250 mL) was added TFA (15 mL) dropwise and theresulting solution was stirred at rt for 3 hours. The desired compoundwas then precipitated out of solution with a mixture of EtOAC:Hexanes(5:20), filtered off and dried under reduced pressure.(R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a whitesolid (0.59 g, 86%) and used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m,2H) 12.65 (s, 1H). LC-MS: Anal. Calcd. for C₁₁H₁₄N₂O₃: 222.24. found:223.21 (M+H)⁺. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water,90% methanol, 0.2% H₃PO₄, RT=0.75 min, 93% homogeneity index.

Step 1: (R)-tert-Butyl 2-(3-cyclopentylureido)-2-phenylacetate. To astirred solution of (R)-2-amino-2-phenylacetic acid hydrochloride (1.0g, 4.10 mmol) and Hunig's base (1.0 mL, 6.15 mmol) in DMF (15 mL) wasadded cyclopentyl isocyanate (0.46 mL, 4.10 mmol) dropwise and over 10minutes. After stirring at room temperature for 3 hours, the reactionwas concentrated under reduced pressure and the resulting residue wastaken up in ethyl acetate. The organic layer was washed with H₂O andbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.(R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate was obtained asan opaque oil (1.32 g; 100%) and used without further purification. ¹HNMR (500 MHz, CD₃Cl-D) δ ppm 1.50-1.57 (m, 2H) 1.58-1.66 (m, 2H)1.87-1.97 (m, 2H) 3.89-3.98 (m, 1H) 5.37 (s, 1H) 7.26-7.38 (m, 5H).LC-MS: Anal. Calcd. for C₁₈H₂₆N₂O₃ 318.19 found 319.21 (M+H)⁺; HPLCXTERRA® C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time,A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1%TFA, RT=2.82 min, 96% homogeneity index.

Step 2: (R)-2-(3-Cyclopentylureido)-2-phenylacetic acid. To a stirredsolution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31g, 4.10 mmol) in CH₂Cl₂ (25 mL) was added TFA (4 mL) and trietheylsilane(1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred atroom temperature for 6 hours. The volatile components were removed underreduced pressure and the crude product was recrystallized in ethylacetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylaceticacid as a white solid (0.69 g, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H)3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48(d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LC-MS: Anal. Calcd.for C₁₄H₁₈N₂O₃: 262.31. found: 263.15 (M+H)⁺. HPLC XTERRA® C-18 3.0×50mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10%methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2% H₃PO₄, RT=1.24min, 100% homogeneity index.

To a stirred solution of 2-(benzylamino)acetic acid (2.0 g, 12.1 mmol)in formic acid (91 mL) was added formaldehyde (6.94 mL, 93.2 mmol).After five hours at 70° C., the reaction mixture was concentrated underreduced pressure to 20 mL and a white solid precipitated. Followingfiltration, the mother liquors were collected and further concentratedunder reduced pressure providing the crude product. Purification byreverse-phase preparative HPLC (XTERRA® 30×100 mm, detection at 220 nm,flow rate 35 mL/min, 0 to 35% B over 8 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) provided the titlecompound 2-(benzyl(methyl)-amino)acetic acid as its TFA salt (723 mg,33%) as a colorless wax. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.75 (s, 3H)4.04 (s, 2H) 4.34 (s, 2H) 7.29-7.68 (m, 5H). LC-MS: Anal. Calcd. for:C₁₀H₁₃NO₂ 179.09. found: 180.20 (M+H)⁺.

To a stirred solution of 3-methyl-2-(methylamino)butanoic acid (0.50 g,3.81 mmol) in water (30 mL) was added K₂CO₃ (2.63 g, 19.1 mmol) andbenzyl chloride (1.32 g, 11.4 mmol). The reaction mixture was stirred atambient temperature for 18 hours. The reaction mixture was extractedwith ethyl acetate (30 mL×2) and the aqueous layer was concentratedunder reduced pressure providing the crude product which was purified byreverse-phase preparative HPLC (XTERRA® 30×100 mm, detection at 220 nm,flow rate 40 mL/min, 20 to 80% B over 6 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) to provide2-(benzyl(methyl)amino)-3-methylbutanoic acid, TFA salt (126 mg, 19%) asa colorless wax. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98 (d, 3H) 1.07 (d,3H) 2.33-2.48 (m, 1H) 2.54-2.78 (m, 3H) 3.69 (s, 1H) 4.24 (s, 2H)7.29-7.65 (m, 5H). LC-MS: Anal. Calcd. for: C₁₃H₁₉NO₂ 221.14. found:222.28 (M+H)⁺.

(S)-2-(Methoxycarbonylamino)-3-methylbutanoic acid

Na₂CO₃ (1.83 g, 17.2 mmol) was added to NaOH (33 mL of 1M/H₂O, 33 mmol)solution of L-valine (3.9 g, 33.29 mmol) and the resulting solution wascooled with ice-water bath. Methyl chloroformate (2.8 mL, 36.1 mmol) wasadded dropwise over 15 min, the cooling bath was removed and thereaction mixture was stirred at ambient temperature for 3.25 hr. Thereaction mixture was washed with ether (50 mL, 3×), and the aqueousphase was cooled with ice-water bath and acidified with concentrated HClto a pH region of 1-2, and extracted with CH₂Cl₂ (50 mL, 3×). Theorganic phase was dried (MgSO₄) and evaporated in vacuo to afford Cap-51as a white solid (6 g). ¹H NMR for the dominant rotamer (DMSO-d₆, δ=2.5ppm, 500 MHz): 12.54 (s, 1H), 7.33 (d, J=8.6, 1H), 3.84 (dd, J=8.4, 6.0,1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H). HRMS: Anal. Calcd. for[M+H]⁺ C₇H₁₄NO₄: 176.0923. found 176.0922.

(S)-2-(Methoxycarbonylamino)-3-methylbutanoic acid

DIEA (137.5 mL, 0.766 mol) was added to a suspension of (S)-tert-butyl2-amino-3-methylbutanoate hydrochloride (75.0 g, 0.357 mol) in THF (900mL), and the mixture was cooled to 0° C. (ice/water bath). Methylchloroformate (29.0 mL, 0.375 mol) was added dropwise over 45 min, thecooling bath was removed and the heterogeneous mixture was stirred atambient temperature for 3 h. The solvent was removed under diminishedpressure and the residue partitioned between EtOAc and water (1 L each).The organic layer was washed with H₂O (1 L) and brine (1 L), dried(MgSO₄), filtered and concentrated under diminished pressure. The crudematerial was passed through a plug of silica gel (1 kg), eluting withhexanes (4 L) and 15:85 EtOAc/hexanes (4 L) to afford (S)-tert-butyl2-(methoxycarbonylamino)-3-methylbutanoate as a clear oil (82.0 g, 99%yield). ¹H NMR (500 MHz, DMSO-d₆, δ=2.5 ppm) 7.34 (d, J=8.6, 1 H), 3.77(dd, J=8.6, 6.1, 1 H), 3.53 (s, 3H), 1.94-2.05 (m, 1H), 1.39 (s, 9H),0.83-0.92 (m, 6H). ¹³C-NMR (126 MHz, DMSO-d₆, δ=39.2 ppm) 170.92,156.84, 80.38, 60.00, 51.34, 29.76, 27.62, 18.92, 17.95. LC-MS: [M+Na]⁺254.17.

Trifluoroacetic acid (343 mL, 4.62 mol) and Et₃SiH (142 mL, 0.887 mol)were added sequentially to a solution of (S)-tert-butyl2-(methoxycarbonylamino)-3-methylbutanoate (82.0 g, 0.355 mol) in CH₂Cl₂(675 mL), and the mixture was stirred at ambient temperature for 4 h.The volatile component was removed under diminished pressure and theresultant oil triturated with petroleum ether (600 mL) to afford a whitesolid, which was filtered and washed with hexanes (500 mL) and petroleumether (500 mL). Recrystallization from EtOAc/petroleum ether affordedCap-51 as white flaky crystals (54.8 g, 88% yield). MP=108.5-109.5° C.¹H NMR (500 MHz, DMSO-d₆, δ=2.5 ppm) 12.52 (s, 1H), 7.31 (d, J=8.6, 1H), 3.83 (dd, J=8.6, 6.1, 1 H), 3.53 (s, 3H), 1.94-2.07 (m, 1H), 0.86(dd, J=8.9, 7.0, 6H). ¹³C NMR (126 MHz, DMSO-d₆, δ=39.2 ppm) 173.30,156.94, 59.48, 51.37, 29.52, 19.15, 17.98. LC-MS: [M+H]⁺=176.11. Anal.Calcd. for C₇H₁₃NO₄: C, 47.99; H, 7.48; N, 7.99. Found: C, 48.17; H,7.55; N, 7.99. Optical Rotation: [α]_(D)=−4.16 (12.02 mg/mL; MeOH).Optical purity: >99.5% ee. Note: the optical purity assessment was madeon the methyl ester derivative of Cap-51, which was prepared under astandard TMSCHN₂ (benzene/MeOH) esterification protocol. HPLC analyticalconditions: column, CHIRALPAK® AD-H (4.6×250 mm, 5 μm); solvent, 95%heptane/5% IPA (isocratic); flow rate, 1 mL/min; temperature, 35° C.; UVmonitored at 205 nm.

[Note: Cap-51 could also be purchased from Flamm.]

(S)-2-(Methoxycarbonylamino)propanoic acid

Cap-52 was synthesized from L-alanine according to the proceduredescribed for the synthesis of Cap-51. For characterization purposes, aportion of the crude material was purified by a reverse phase HPLC(H₂O/methanol/TFA) to afford Cap-52 as a colorless viscous oil. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.49 (br s, 1H), 7.43 (d, J=7.3, 0.88H),7.09 (app br s, 0.12H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J=7.3, 3H).

Cap-53 to Cap-64

Cap-53 to Cap-64 were prepared from appropriate starting materialsaccording to the procedure described for the synthesis of Cap-51, withnoted modifications if any.

Cap Structure Data Cap-53a: (R) Cap-53b: (S) ((S)-2- (methoxy-carbonyl-amino)butanoic acid)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.51 (br s, 1H), 7.4 (d, J =7.9, 0.9H), 7.06 (app s, 0.1H), 3.86-3.82 (m, 1H), 3.53 (s, 3H),1.75-1.67 (m, 1H), 1.62- 1.54 (m, 1H), 0.88 (d, J = 7.3, 3H). RT = 0.77minutes (Cond. 2); LC-MS: Anal. Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄: 184.06;found 184.07. HRMS Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄: 184.0586; found184.0592. Cap-54a: (R) Cap-54b: (S) ((S)-2- cyclopropyl-2-(methoxy-carbonyl- amino)acetic acid)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.48 (s, 1H), 7.58 (d, J =7.6, 0.9H), 7.25 (app s, 0.1H), 3.52 (s, 3H), 3.36-3.33 (m, 1H),1.10-1.01 (m, 1H), 0.54- 0.49 (m, 1H), 0.46-0.40 (m, 1H), 0.39-0.35 (m,1H), 0.31-0.21 (m, 1H). HRMS Calcd. for [M + H]⁺ C₇H₁₂NO₄: 174.0766;found 174.0771 Cap-55

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.62 (s, 1H), 7.42 (d, J =8.2, 0.9H), 7.07 (app s, 0.1H), 5.80-5.72 (m, 1H), 5.10 (d, J = 17.1,1H), 5.04 (d, J = 10.4, 1H), 4.01-3.96 (m, 1H), 3.53 (s, 3H), 2.47-2.42(m, 1H), 2.35-2.29 (m, 1H). Cap-56 (S)-3-methoxy-2- (methoxy-carbonyl-amino)propanoic acid

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.75 (s, 1H), 7.38 (d, J =8.3, 0.9H), 6.96 (app s, 0.1H), 4.20-4.16 (m, 1H), 3.60-3.55 (m, 2H),3.54 (s, 3H), 3.24 (s, 3H). Cap-57

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.50 (s, 1H), 8.02 (d, J =7.7, 0.08H), 7.40 (d, J = 7.9, 0.76H), 7.19 (d, J = 8.2, 0.07H), 7.07(d, J = 6.7, 0.09H), 4.21-4.12 (m, 0.08H), 4.06-3.97 (m, 0.07H),3.96-3.80 (m, 0.85H), 3.53 (s, 3H), 1.69- 1.51 (m, 2H), 1.39-1.26 (m,2H), 0.85 (t, J = 7.4, 3H). LC (Cond. 2): RT = 1.39 LC- MS: Anal. Calcd.for [M + H]⁺ C₇H₁₄NO₄: 176.09; found 176.06. Cap-58

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.63 (br s, 1H), 7.35 (s,1H), 7.31 (d, J = 8.2, 1H), 6.92 (s, 1H), 4.33-4.29 (m, 1H), 3.54 (s,3H), 2.54(dd, J = 15.5, 5.4, 1H), 2.43 (dd, J = 15.6, 8.0, 1H). RT =0.16 min (Cond. 2); LC-MS: Anal. Calcd. for [M + H]⁺ C₆H₁₁N₂O₅: 191.07;found 191.14. Cap-59a: (R) Cap-59b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.49 (br s, 1H), 7.40 (d, J =7.3, 0.89H), 7.04 (br s, 0.11H), 4.00-3.95 (m, 3H), 1.24 (d, J = 7.3,3H), 1.15 (t, J = 7.2, 3H). HRMS: Anal. Calcd. for [M + H]⁺ C₆H₁₂NO₄:162.0766; found 162.0771. Cap-60

The crude material was purified with a reverse phase HPLC (H₂O/MeOH/TFA)to afford a colorless viscous oil that crystallized to a white solidupon exposure to high vacuum. ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ12.38 (br s, 1H), 7.74 (s, 0.82H), 7.48 (s, 0.18H), 3.54/3.51 (two s,3H), 1.30 (m, 2H), 0.98 (m, 2H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₀NO₄: 160.0610; found 160.0604. Cap-61

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.27 (br s, 1H), 7.40 (br s,1H), 3.50 (s, 3H), 1.32 (s, 6H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₂NO₄: 162.0766; found 162.0765. Cap-62

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.74 (br s, 1H), 4.21 (d, J =10.3, 0.6H), 4.05 (d, J = 10.0, 0.4H), 3.62/3.60 (two singlets, 3H), 3.0(s, 3H), 2.14-2.05 (m, 1H), 0.95 (d, J = 6.3, 3H), 0.81 (d, J = 6.6,3H). LC-MS: Anal. Calcd. for [M − H]⁻ C₈H₁₄NO₄: 188.09; found 188.05.Cap-63

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz):12.21 (br s, 1H), 7.42 (br s, 1H), 3.50 (s, 3H), 2.02-1.85 (m, 4H),1.66-1.58 (m, 4H). LC-MS: Anal. Calcd. for [M + H]⁺ C₈H₁₄NO₄: 188.09;found 188.19. Cap-64

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz):12.35 (br s, 1H), 7.77 (s, 0.82H), 7.56/7.52 (overlapping br s, 0.18H),3.50 (s, 3H), 2.47-2.40 (m, 2H), 2.14-2.07 (m, 2H), 1.93-1.82 (m, 2H).

Methyl chloroformate (0.65 mL, 8.39 mmol) was added dropwise over 5 minto a cooled (ice-water) mixture of Na₂CO₃ (0.449 g, 4.23 mmol), NaOH(8.2 mL of 1M/H₂O, 8.2 mmol) and (S)-2-amino-3-hydroxy-3-methylbutanoicacid (1.04 g, 7.81 mmol). The reaction mixture was stirred for 45 min,and then the cooling bath was removed and stirring was continued for anadditional 3.75 hr. The reaction mixture was washed with CH₂Cl₂, and theaqueous phase was cooled with ice-water bath and acidified withconcentrated HCl to a pH region of 1-2. The volatile component wasremoved in vacuo and the residue was taken up in a 2:1 mixture ofMeOH/CH₂Cl₂ (15 mL) and filtered, and the filterate was rotervaped toafford Cap-65 as a white semi-viscous foam (1.236 g). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 400 MHz): δ 6.94 (d, J=8.5, 0.9H), 6.53 (br s, 0.1H), 3.89(d, J=8.8, 1H), 2.94 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H).

Cap-66 and Cap-67 were prepared from appropriate commercially availablestarting materials by employing the procedure described for thesynthesis of Cap-65.

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.58 (br s, 1H), 7.07 (d,J=8.3, 0.13H), 6.81 (d, J=8.8, 0.67H), 4.10-4.02 (m, 1.15H), 3.91 (dd,J=9.1, 3.5, 0.85H), 3.56 (s, 3H), 1.09 (d, J=6.2, 3H). [Note: only thedominant signals of NH were noted].

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 12.51 (br s, 1H), 7.25 (d, J=8.4,0.75H), 7.12 (br d, J=0.4, 0.05H), 6.86 (br s, 0.08H), 3.95-3.85 (m,2H), 3.54 (s, 3H), 1.08 (d, J=6.3, 3H). [Note: only the dominant signalsof NH were noted].

Methyl chloroformate (0.38 ml, 4.9 mmol) was added drop-wise to amixture of 1N NaOH (aq) (9.0 ml, 9.0 mmol), 1M NaHCO₃ (aq) (9.0 ml, 9.0mol), L-aspartic acid β-benzyl ester (1.0 g, 4.5 mmol) and Dioxane (9ml). The reaction mixture was stirred at ambient conditions for 3 hr,and then washed with Ethyl acetate (50 ml, 3×). The aqueous layer wasacidified with 12N HCl to a pH˜1-2, and extracted with ethyl acetate(3×50 ml). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to afford Cap-68 as alight yellow oil (1.37 g; mass is above theoretical yield, and theproduct was used without further purification). ¹H NMR (DMSO-d₆, δ=2.5ppm, 500 MHz): δ 12.88 (br s, 1H), 7.55 (d, J=8.5, 1H), 7.40-7.32 (m,5H), 5.13 (d, J=12.8, 1H), 5.10 (d, J=12.9, 1H), 4.42-4.38 (m, 1H), 3.55(s, 3H), 2.87 (dd, J=16.2, 5.5, 1H), 2.71 (dd, J=16.2, 8.3, 1H). LC(Cond. 2): RT=1.90 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₆NO₆:282.10. found 282.12.

NaCNBH₃ (2.416 g, 36.5 mmol) was added in batches to a chilled (˜15° C.)water (17 mL)/MeOH (10 mL) solution of alanine (1.338 g, 15.0 mmol). Afew minutes later acetaldehyde (4.0 mL, 71.3 mmol) was added drop-wiseover 4 min, the cooling bath was removed, and the reaction mixture wasstirred at ambient condition for 6 hr. An additional acetaldehyde (4.0mL) was added and the reaction was stirred for 2 hr. Concentrated HClwas added slowly to the reaction mixture until the pH reached ˜1.5, andthe resulting mixture was heated for 1 hr at 40° C. Most of the volatilecomponent was removed in vacuo and the residue was purified with aDOWEX® 50WX8-100 ion-exchange resin (column was washed with water, andthe compound was eluted with dilute NH₄OH, prepared by mixing 18 ml ofNH₄OH and 282 ml of water) to afford Cap-69 (2.0 g) as an off-white softhygroscopic solid. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 3.44 (q,J=7.1, 1H), 2.99-2.90 (m, 2H), 2.89-2.80 (m, 2H), 1.23 (d, J=7.1, 3H),1.13 (t, J=7.3, 6H).

Cap-70 to Cap-74x

Cap-70 to Cap-74x were prepared according to the procedure described forthe synthesis of Cap-69 by employing appropriate starting materials.

Cap-70a: (R) Cap-70b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 3.42 (q, J = 7.1, 1H),2.68-2.60 (m, 4H), 1.53-1.44 (m, 4H), 1.19 (d, J = 7.3, 3H), 0.85 (t, J= 7.5, 6H). LC- MS: Anal. Calcd. for [M + H]⁺ C₉H₂₀NO₂: 174.15; found174.13. Cap-71a: (R) Cap-71b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 3.18- 3.14 (m, 1H), 2.84-2.77(m, 2H), 2.76-2.68 (m, 2H), 1.69-1.54 (m, 2H), 1.05 (t, J = 7.2, 6H),0.91 (t, J = 7.3, 3H). LC-MS: Anal. Calcd. for [M + H]⁺ C₈H₁₈NO₂:160.13; found 160.06. Cap-72

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 2.77- 2.66 (m, 3H), 2.39-2.31(m, 2H), 1.94-1.85 (m, 1H), 0.98 (t, J = 7.1, 6H), 0.91 (d, J = 6.5,3H), 0.85 (d, J = 6.5, 3H). LC-MS: Anal. Calcd. for [M + H]⁺ C₉H₂₀NO₂:174.15; found 174.15. Cap-73

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 9.5 (br s, 1H), 3.77 (dd, J =10.8, 4.1, 1H), 3.69-3.61 (m, 2H), 3.26 (s, 3H), 2.99-2.88 (m, 4H), 1.13(t, J = 7.2, 6H). Cap-74

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 7.54 (s, 1H), 6.89 (s, 1H),3.81 (t, J = 6.6, k, 1H), 2.82- 2.71 (m, 4H), 2.63 (dd, J = 15.6, 7.0,1H), 2.36 (dd, J = 15.4, 6.3, 1H), 1.09 (t, J = 7.2, 6H). RT = 0.125minutes (Cond. 2); LC-MS: Anal. Calcd. for [M + H]⁺ C₈H₁₇N₂O₃: 189.12;found 189.13. Cap-74x

LC-MS: Anal. Calcd. for [M + H]⁺ C₁₀H₂₂NO₂: 188.17; found 188.21

NaBH₃CN (1.6 g, 25.5 mmol) was added to a cooled (ice/water bath) water(25 ml)/methanol (15 ml) solution of H-D-Ser-OBzl HCl (2.0 g, 8.6 mmol).Acetaldehyde (1.5 ml, 12.5 mmol) was added drop-wise over 5 min, thecooling bath was removed, and the reaction mixture was stirred atambient condition for 2 hr. The reaction was carefully quenched with 12NHCl and concentrated in vacuo. The residue was dissolved in water andpurified with a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA saltof (R)-benzyl 2-(diethylamino)-3-hydroxypropanoate as a colorlessviscous oil (1.9 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): δ 9.73 (br s,1H), 7.52-7.36 (m, 5H), 5.32 (d, J=12.2, 1H), 5.27 (d, J=12.5, 1H),4.54-4.32 (m, 1H), 4.05-3.97 (m, 2H), 3.43-3.21 (m, 4H), 1.23 (t, J=7.2,6H). LC-MS (Cond. 2): RT=1.38 min; LC-MS: Anal. Calcd. for [M+H]⁺C₁₄H₂₂NO₃: 252.16. found 252.19.

Cap-75

NaH (0.0727 g, 1.82 mmol, 60%) was added to a cooled (ice-water) THF(3.0 mL) solution of the TFA salt (R)-benzyl2-(diethylamino)-3-hydroxypropanoate (0.3019 g, 0.8264 mmol) preparedabove, and the mixture was stirred for 15 min. Methyl iodide (56 μL,0.90 mmol) was added and stirring was continued for 18 hr while allowingthe bath to thaw to ambient condition. The reaction was quenched withwater and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, andwashed with methanol followed by compound elution with 2N NH₃/Methanol.Removal of the volatile component in vacuo afforded Cap-75, contaminatedwith (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellowsemi-solid (100 mg). The product was used as is without furtherpurification.

NaCNBH₃ (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.)water/MeOH (12 mL each) solution of(S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was addeddrop-wise over 2 min, the cooling bath was removed, and the reactionmixture was stirred at ambient condition for 3.5 hr. An additionalacetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirredfor 20.5 hr. Most of the MeOH component was removed in vacuo, and theremaining mixture was treated with concentrated HCl until its pH reached˜1.0 and then heated for 2 hr at 40° C. The volatile component wasremoved in vacuo, and the residue was treated with 4 M HCl/dioxane (20mL) and stirred at ambient condition for 7.5 hr. The volatile componentwas removed in vacuo and the residue was purified with DOWEX® 50WX8-100ion-exchange resin (column was washed with water and the compound waseluted with dilute NH₄OH, prepared from 18 ml of NH₄OH and 282 ml ofwater) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acidas an off-white solid (1.73 g).

Methyl chloroformate (0.36 mL, 4.65 mmol) was added drop-wise over 11min to a cooled (ice-water) mixture of Na₂CO₃ (0.243 g, 2.29 mmol), NaOH(4.6 mL of 1M/H₂O, 4.6 mmol) and the above product (802.4 mg). Thereaction mixture was stirred for 55 min, and then the cooling bath wasremoved and stirring was continued for an additional 5.25 hr. Thereaction mixture was diluted with equal volume of water and washed withCH₂Cl₂ (30 mL, 2×), and the aqueous phase was cooled with ice-water bathand acidified with concentrated HCl to a pH region of 2. The volatilecomponent was then removed in vacuo and the crude material wasfree-based with MCX resin (6.0 g; column was washed with water, andsample was eluted with 2.0 M NH₃/MeOH) to afford impure Cap-76 as anoff-white solid (704 mg). ¹H NMR (MeOH-d₄, δ=3.29 ppm, 400 MHz): δ 3.99(dd, J=7.5, 4.7, 1H), 3.62 (s, 3H), 3.25-3.06 (m, 6H), 2.18-2.09 (m,1H), 2.04-1.96 (m, 1H), 1.28 (t, J=7.3, 6H). LC-MS: Anal. Calcd. for[M+H]⁺ C₁₀H₂₁N₂O₄: 233.15. found 233.24.

The synthesis of Cap-77 was conducted according to the proceduredescribed for Cap-7 by using 7-azabicyclo[2.2.1]heptane for the SN₂displacement step, and by effecting the stereoisomeric separation of theintermediate benzyl 2-(7-azabicyclo[2.2.1]heptan-7-yl)-2-phenylacetateusing the following condition: the intermediate (303.7 mg) was dissolvedin ethanol, and the resulting solution was injected on a chiral HPLCcolumn (Chiracel AD-H column, 30×250 mm, 5 um) eluting with 90% CO₂-10%EtOH at 70 mL/min, and a temperature of 35° C. to provide 124.5 mg ofstereoisomer-1 and 133.8 mg of stereoisomer-2. These benzyl esters werehydrogenolysed according to the preparation of Cap-7 to provide Cap-77:¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.55 (m, 2H), 7.38-7.30 (m, 3H),4.16 (s, 1H), 3.54 (app br s, 2H), 2.08-1.88 (m, 4H), 1.57-1.46 (m, 4H).LC (Cond. 1): RT=0.67 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₄H₁₈NO₂:232.13. found 232.18. HRMS: Anal. Calcd. for [M+H]⁺ C₁₄H₁₈NO₂: 232.1338.found 232.1340.

NaCNBH₃ (0.5828 g, 9.27 mmol) was added to a mixture of the HCl salt of(R)-2-(ethylamino)-2-phenylacetic acid (an intermediate in the synthesisof Cap-3; 0.9923 mg, 4.60 mmol) and(1-ethoxycyclopropoxy)trimethylsilane (1.640 g, 9.40 mmol) in MeOH (10mL), and the semi-heterogeneous mixture was heated at 50° C. with an oilbath for 20 hr. More (1-ethoxycyclopropoxy)trimethylsilane (150 mg, 0.86mmol) and NaCNBH₃ (52 mg, 0.827 mmol) were added and the reactionmixture was heated for an additional 3.5 hr. It was then allowed to coolto ambient temperature and acidified to a ˜pH region of 2 withconcentrated HCl, and the mixture was filtered and the filtrate wasrotervaped. The resulting crude material was taken up in i-PrOH (6 mL)and heated to effect dissolution, and the non-dissolved part wasfiltered off and the filtrate concentrated in vacuo. About ⅓ of theresultant crude material was purified with a reverse phase HPLC(H₂O/MeOH/TFA) to afford the TFA salt of Cap-78 as a colorless viscousoil (353 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz; after D₂O exchange):δ 7.56-7.49 (m, 5H), 5.35 (S, 1H), 3.35 (m, 1H), 3.06 (app br s, 1H),2.66 (m, 1H), 1.26 (t, J=7.3, 3H), 0.92 (m, 1H), 0.83-0.44 (m, 3H). LC(Cond. 1): RT=0.64 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂:220.13. found 220.21. HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂: 220.1338.found 220.1343.

Ozone was bubbled through a cooled (−78° C.) CH₂Cl₂ (5.0 mL) solutionCap-55 (369 mg, 2.13 mmol) for about 50 min until the reaction mixtureattained a tint of blue color. Me₂S (10 pipet drops) was added, and thereaction mixture was stirred for 35 min. The −78° C. bath was replacedwith a −10° C. bath and stirring continued for an additional 30 min, andthen the volatile component was removed in vacuo to afford a colorlessviscous oil.

NaBH₃CN (149 mg, 2.25 mmol) was added to a MeOH (5.0 mL) solution of theabove crude material and morpholine (500 μL, 5.72 mmol) and the mixturewas stirred at ambient condition for 4 hr. It was cooled to ice-watertemperature and treated with concentrated HCl to bring its pH to ˜2.0,and then stirred for 2.5 hr. The volatile component was removed invacuo, and the residue was purified with a combination of MCX resin(MeOH wash; 2.0 N NH₃/MeOH elution) and a reverse phase HPLC(H₂O/MeOH/TFA) to afford Cap-79 containing unknown amount of morpholine.

In order to consume the morpholine contaminant, the above material wasdissolved in CH₂Cl₂ (1.5 mL) and treated with Et₃N (0.27 mL, 1.94 mmol)followed by acetic anhydride (0.10 mL, 1.06 mmol) and stirred at ambientcondition for 18 hr. THF (1.0 mL) and H₂O (0.5 mL) were added andstirring continued for 1.5 hr. The volatile component was removed invacuo, and the resultant residue was passed through MCX resin (MeOHwash; 2.0 N NH₃/MeOH elution) to afford impure Cap-79 as a brown viscousoil, which was used for the next step without further purification.

SOCl₂ (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled(ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid(10.04 g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removedand the reaction mixture was stirred at ambient condition for 29 hr.Most of the volatile component was removed in vacuo and the residue wascarefully partitioned between EtOAc (150 mL) and saturated NaHCO₃solution. The aqueous phase was extracted with EtOAc (150 mL, 2×), andthe combined organic phase was dried (MgSO₄), filtered, and concentratedin vacuo to afford (S)-1-benzyl 4-methyl 2-aminosuccinate as a colorlessoil (9.706 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.40-7.32 (m,5H), 5.11 (s, 2H), 3.72 (app t, J=6.6, 1H), 3.55 (s, 3H), 2.68 (dd,J=15.9, 6.3, 1H), 2.58 (dd, J=15.9, 6.8, 1H), 1.96 (s, 2H). LC (Cond.1): RT=0.90 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₆NO₄: 238.11. found238.22.

Pb(NO₃)₂ (6.06 g, 18.3 mmol) was added over 1 min to a CH₂Cl₂ (80 mL)solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol),9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et₃N (3.0 mL, 21.5mmol), and the heterogeneous mixture was stirred at ambient conditionfor 48 hr. The mixture was filtered and the filtrate was treated withMgSO₄ and filtered again, and the final filtrate was concentrated. Theresulting crude material was submitted to a BIOTAGE® purification (350 gsilica gel, CH₂Cl₂ elution) to afford (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorlessoil (7.93 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H),7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d,J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partiallyoverlapped with solvent). LC (Cond. 1): RT=2.16 min; LC-MS: Anal. Calcd.for [M+H]⁺ C₃₁H₂₈NO₄: 478.20. found 478.19.

LiHMDS (9.2 mL of 1.0 M/THF, 9.2 mmol) was added drop-wise over 10 minto a cooled (−78° C.) THF (50 mL) solution of (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.907 g, 8.18 mmol) andstirred for ˜1 hr. MeI (0.57 mL, 9.2 mmol) was added drop-wise over 8min to the mixture, and stirring was continued for 16.5 hr whileallowing the cooling bath to thaw to room temperature. After quenchingwith saturated NH₄Cl solution (5 mL), most of the organic component wasremoved in vacuo and the residue was partitioned between CH₂Cl₂ (100 mL)and water (40 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo, and the resulting crude material was purifiedwith a BIOTAGE® (350 g silica gel; 25% EtOAc/hexanes) to afford 3.65 gof a 2S/3S and 2S/3R diastereomeric mixtures of 1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate in ˜1.0:0.65 ratio(¹H NMR). The stereochemistry of the dominant isomer was not determinedat this juncture, and the mixture was submitted to the next step withoutseparation. Partial ¹H NMR data (DMSO-d₆, δ=2.5 ppm, 400 MHz): majordiastereomer, δ 4.39 (d, J=12.3, 1H of CH₂), 3.33 (s, 3H, overlappedwith H₂O signal), 3.50 (d, J=10.9, NH), 1.13 (d, J=7.1, 3H); minordiastereomer, δ 4.27 (d, J=12.3, 1H of CH₂), 3.76 (d, J=10.9, NH), 3.64(s, 3H), 0.77 (d, J=7.0, 3H). LC (Cond. 1): RT=2.19 min; LC-MS: Anal.Calcd. for [M+H]⁺ C₃₂H₃₀NO₄: 492.22. found 492.15.

Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol)was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL)solution of (2S)-1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol)prepared above, and stirred at −78° C. for 20 hr. The reaction mixturewas removed from the cooling bath and rapidly poured into ˜1M H₃PO₄/H₂O(250 mL) with stirring, and the mixture was extracted with ether (100mL, 2×). The combined organic phase was washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. A silica gel mesh of thecrude material was prepared and submitted to chromatography (25%EtOAc/hexanes; gravity elution) to afford 1.1 g of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with benzyl alcohol, as a colorless viscous oil and(2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containingthe (2S,3R) stereoisomer as an impurity. The later sample wasresubmitted to the same column chromatography purification conditions toafford 750 mg of purified material as a white foam. [Note: the (2S,3S)isomer elutes before the (2S,3R) isomer under the above condition].(2S,3S) isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H),7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 1H), 4.21(app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H),˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d,J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC-MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45. found 464.22. (2S,3R) isomer: ¹H NMR (DMSO-d₆, δ=2.5ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1,1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 1H), 3.59-3.53 (m, 2H),3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8,3H). LC (Cond. 1): RT=1.92 min; LC-MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45. found 464.52.

The relative stereochemical assignments of the DIBAL-reduction productswere made based on NOE studies conducted on lactone derivatives preparedfrom each isomer by employing the following protocol: LiHMDS (50 μL of1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL)solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg,0.135 mmol), and the reaction mixture was stirred at similar temperaturefor ˜2 hr. The volatile component was removed in vacuo and the residuewas partitioned between CH₂Cl₂ (30 mL), water (20 mL) and saturatedaqueous NH₄Cl solution (1 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo, and the resulting crude materialwas submitted to a BIOTAGE® purification (40 g silica gel; 10-15%EtOAc/hexanes) to afford(3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-oneas a colorless film of solid (28.1 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to(3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one.(3S,4S)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.83 (d,J=7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J=8.3, 1H), 3.60 (d, J=5.8,NH), 3.45 (app t, J=9.2, 1H), ˜2.47 (m, 1H, partially overlapped withsolvent signal), 2.16 (m, 1H), 0.27 (d, J=6.6, 3H). LC (Cond. 1):RT=1.98 min; LC-MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15. found378.42. (3S,4R)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz),7.89 (d, J=7.6, 1H), 7.85 (d, J=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd,J=9.1, 4.8, 1H), 3.76 (d, J=8.8, 1H), 2.96 (d, J=3.0, NH), 2.92 (dd,J=6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0, 3H). LC (Cond. 1): RT=2.03min; LC-MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15. found 378.49.

TBDMS-Cl (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol)were added to a CH₂Cl₂ (3 ml) solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg,0.258 mmol), and the mixture was stirred at ambient condition for 14.25hr. The reaction mixture was then diluted with CH₂Cl₂ (30 mL) and washedwith water (15 mL), and the organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. The resultant crude material was purifiedwith a BIOTAGE® (40 g silica gel; 5% EtOAc/hexanes) to afford(2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with TBDMS based impurities, as a colorless viscous oil(124.4 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate.(2S,3S)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.82(d, J=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m, 16H), 4.70 (d,J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1,5.5, 1H), 1.61 (m, 1H), 0.90 (d, J=6.8, 3H), 0.70 (s, 9H), −0.13 (s,3H), −0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4min): RT=3.26 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₃₇H₄₄NO₃Si: 578.31.found 578.40. (2S,3R)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 7.82 (d, J=3.0, 1H), 7.80 (d, J=3.1, 1H), 7.39-7.10 (m, 16H),4.66 (d, J=12.4, 1H), 4.39 (d, J=12.4, 1H), 3.61 (dd, J=9.9, 5.6, 1H),3.45 (d, J=9.5, 1H), 3.41 (dd, J=10, 6.2, 1H), 2.55 (dd, J=9.5, 7.3,1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1, 3H), −0.06 (s, 3H),−0.08 (s, 3H).

A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate(836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and themixture was stirred at room temperature for ˜21 hr, where the balloonwas recharged with H₂ as necessary. The reaction mixture was dilutedwith CH₂Cl₂ and filtered through a pad of diatomaceous earth(CELITE®-545), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH(1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase wasconcentrated, and a silica gel mesh was prepared from the resultingcrude material and submitted to a flash chromatography (8:2:1 mixture ofEtOAc/i-PrOH/H₂O) to afford(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid asa white fluffy solid (325 mg). (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoatewas similarly elaborated to(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid.(2S,3S)-amino acid isomer: ¹H NMR (methanol-d₄, δ=3.29 ppm, 400 MHz),3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0,1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H).LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si: 248.17. found 248.44.(2S,3R)-amino acid isomer: ¹H NMR (methanol-d₄, δ=3.29 ppm, 400 MHz),3.76-3.75 (m, 2H), 3.60 (d, J=4.1, 1H), 2.16 (m, 1H), 1.06 (d, J=7.3,3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si:248.17. found 248.44.

Water (1 mL) and NaOH (0.18 mL of 1.0 M/H₂O, 0.18 mmol) were added to amixture of(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid(41.9 mg, 0.169 mmol) and Na₂CO₃ (11.9 mg, 0.112 mmol), and sonicatedfor about 1 min to effect dissolution of reactants. The mixture was thencooled with an ice-water bath, methyl chloroformate (0.02 mL, 0.259mmol) was added over 30 s, and vigorous stirring was continued atsimilar temperature for 40 min and then at ambient temperature for 2.7hr. The reaction mixture was diluted with water (5 mL), cooled withice-water bath and treated drop-wise with 1.0 N HCl aqueous solution(˜0.23 mL). The mixture was further diluted with water (10 mL) andextracted with CH₂Cl₂ (15 mL, 2×). The combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo to afford Cap-80a as anoff-white solid.(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid wassimilarly elaborated to Cap-80b. Cap-80a: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 12.57 (br s, 1H), 7.64 (d, J=8.3, 0.3H), 7.19 (d, J=8.8,0.7H), 4.44 (dd, J=8.1, 4.6, 0.3H), 4.23 (dd, J=8.7, 4.4, 0.7H),3.56/3.53 (two singlets, 3H), 3.48-3.40 (m, 2H), 2.22-2.10 (m, 1H), 0.85(s, 9H), ˜0.84 (d, 0.9H, overlapped with t-Bu signal), 0.79 (d, J=7,2.1H), 0.02/0.01/0.00 (three overlapping singlets, 6H). LC-MS: Anal.Calcd. for [M+Na]⁺ C₁₃H₂₇NNaO₅Si: 328.16. found 328.46. Cap-80b: ¹H NMR(CDCl₃, δ=7.24 ppm, 400 MHz), 6.00 (br d, J=6.8, 1H), 4.36 (dd, J=7.1,3.1, 1H), 3.87 (dd, J=10.5, 3.0, 1H), 3.67 (s, 3H), 3.58 (dd, J=10.6,4.8, 1H), 2.35 (m, 1H), 1.03 (d, J=7.1, 3H), 0.90 (s, 9H), 0.08 (s, 6H).LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₃H₂₇NNaO₅Si: 328.16. found 328.53. Thecrude products were utilized without further purification.

Prepared according to the protocol described by Falb et al., SyntheticCommunications, 23:2839 (1993).

Cap-82 to Cap-85

Cap-82 to Cap-85 were synthesized from appropriate starting materialsaccording to the procedure described for Cap-51 or Cap-13. The samplesexhibited similar spectral profiles as that of their stereoisomers(i.e., Cap-4, Cap-13, Cap-51 and Cap-52, respectively).

(2S,3R)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid

To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g,22.55 mmol) in H₂O (15 mL) was added ClCO₂Me (1.74 mL, 22.55 mmol)dropwise at 0° C. The mixture was allowed to stir for 12 h and acidifiedto pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc and(2×250 mL) and 10% MeOH in CH₂Cl₂ (250 mL) and the combined organicphases were concentrated under in vacuo to afford a colorless oil (4.18g, 97%) which was of sufficient purity for use in subsequent steps. ¹HNMR (400 MHz, CDCl₃) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H),1.17 (d, J=7.7 Hz, 3H). LC-MS: Anal. Calcd. for C₇H₁₃NO₅: 191. found:190 (M−H)⁻.

To a mixture of L-homoserine (2.0 g, 9.79 mmol), Na₂CO₃ (2.08 g, 19.59mmol) in H₂O (15 mL) was added ClCO₂Me (0.76 mL, 9.79 mmol) dropwise at0° C. The mixture was allowed to stir for 48 h and acidified to pH 1using 1N HCl. The aqueous phase was extracted with EtOAc and (2×250 mL)and the combined organic phases were concentrated in vacuo to afford acolorless solid (0.719 g, 28%) which was of sufficient purity for use insubsequent steps. ¹H NMR (400 MHz, CDCl₃) δ 4.23 (dd, J=4.5, 9.1 Hz,1H), 3.66 (s, 3H), 3.43-3.49 (m, 2H), 2.08-2.14 (m, 1H), 1.82-1.89 (m,1H). LC-MS: Anal. Calcd. for C₇H₁₃NO₅: 191. found: 192 (M+H)⁺.

A mixture of L-valine (1.0 g, 8.54 mmol), 3-bromopyridine (1.8 mL, 18.7mmol), K₂CO₃ (2.45 g, 17.7 mmol) and CuI (169 mg, 0.887 mmol) in DMSO(10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooledto rt, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2). Theorganic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophyllized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.00 (s, br, 1H), 7.68-7.71 (m, 1H), 7.01 (s, br, 1H), 6.88(d, J=7.5 Hz, 1H), 5.75 (s, br, 1H), 3.54 (s, 1H), 2.04-2.06 (m, 1H),0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H). LC-MS: Anal. Calcd. forC₁₀H₁₄N₂O₂: 194. found: 195 (M+H)⁺.

A mixture of L-valine (1.0 g, 8.54 mmol), 5-bromopyrimidine (4.03 g,17.0 mmol), K₂CO₃ (2.40 g, 17.4 mmol) and CuI (179 mg, 0.94 mmol) inDMSO (10 mL) was heated at 100° C. for 12 h. The reaction mixture wascooled to RT, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2).The organic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophyllized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹H NMR (400 MHz,CD₃OD) showed the mixture to contain valine and the purity could not beestimated. The material was used as is in subsequent reactions. LC-MS:Anal. Calcd. for C₉H₁₃N₃O₂: 195. found: 196 (M+H)⁺.

Cap-90 was prepared according to the method described for thepreparation of Cap-1. The crude material was used as is in subsequentsteps. LC-MS: Anal. Calcd. for C₁₁H₁₅NO₂: 193. found: 192 (M−H)⁻.

Cap-91 to Cap-116

The following Caps were prepared according to the method used forpreparation of Cap-51 unless noted otherwise:

Cap Structure LC-MS Cap-91

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-92

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: CO₂H 223; found: 222 (M − H)⁻. Cap-93

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-94

LC-MS: Anal. Calcd. for C₈H₁₁N₃O₄: 213; found: 214 (M + H)⁺. Cap-95

LC-MS: Anal. Calcd. for C₁₃H₁₇NO₄: 251; found: 250 (M − H)⁻. Cap-96

LC-MS: Anal. Calcd. for C₁₂H₁₅NO₄: 237; found: 236 (M − H)⁻. Cap-97

LC-MS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 200 (M − H)⁻. Cap-98

LC-MS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 202 (M + H)⁺. Cap-99

¹H NMR (400 MHz, CD₃OD) δ 3.88- 3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80(m, 1H), 2.20 (m 1H), 1.82-1.94 (m, 3H), 1.45-1.71 (m, 2H). Cap-99a

¹H NMR (400 MHz, CD₃OD) δ 3.88- 3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80(m, 1H), 2.20 (m 1H), 1.82-1.94 (m, 3H), 1.45-1.71 (m, 2H). Cap-100

LC-MS: Anal. Calcd. for C₁₂H₁₄NO₄F: 255; found: 256 (M + H)⁺. Cap-101

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-102

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻ Cap-103

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-104

¹H NMR (400 MHz, CD₃OD) δ 3.60 (s, 3H), 3.50-3.53 (m, 1H), 2.66-2.69 and2.44-2.49 (m, 1H), 1.91-2.01 (m, 2H), 1.62-1.74 (m, 4H), 1.51-1.62 (m,2H). Cap-105

¹H NMR (400 MHz, CD₃OD) δ 3.60 (s, 3H), 3.33-3.35 (m, 1H, partiallyobscured by solvent), 2.37-2.41 and 2.16-2.23 (m, 1H), 1.94-2.01 (m,4H), 1.43-1.53 (m, 2H), 1.17-1.29 (m, 2H). Cap-106

¹H NMR (400 MHz, CD₃OD) δ 3.16 (q, J = 7.3 Hz, 4H), 2.38-2.41 (m, 1H),2.28-2.31 (m, 2H), 1.79-1.89 (m, 2H), 1.74 (app, ddd J = 3.5, 12.5, 15.9Hz, 2H), 1.46 (app dt J = 4.0, 12.9 Hz, 2H), 1.26 (t, J = 7.3 Hz, 6H)Cap-107

LC-MS: Anal. Calcd. for C₈H₁₀N₂O₄S: 230; found: 231 (M + H)⁺. Cap-108

LC-MS: Anal. Calcd. for C₁₅H₁₇N₃O₄: 303; found: 304 (M + H)⁺. Cap-109

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-110

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-111

LC-MS: Anal. Calcd. for C₁₂H₁₆NO₈P: 333; found: 334 (M + H)⁺. Cap-112

LC-MS: Anal. Calcd. for C₁₃H₁₄N₂O₄: 262; found: 263 (M + H)⁺. Cap-113

LC-MS: Anal. Calcd. for C₁₈H₁₉NO₅: 329; found: 330 (M + H)⁺. Cap-114

¹H NMR (400 MHz, CDCl₃) δ 4.82- 4.84 (m, 1H), 4.00-4.05 (m, 2H), 3.77(s, 3H), 2.56 (s, br, 2H) Cap-115

¹H NMR (400 MHz, CDCl₃) δ 5.13 (s, br, 1H), 4.13 (s, br, 1H), 3.69 (s,3H), 2.61 (d, J = 5.0 Hz, 2H), 1.28 (d, J = 9.1 Hz, 3H). Cap-116

¹H NMR (400 MHz, CDCl₃) δ 5.10 (d, J = 8.6 Hz, 1H), 3.74-3.83 (m, 1H),3.69 (s, 3H), 2.54-2.61 (m, 2H), 1.88 (sept, J = 7.0 Hz, 1H), 0.95 (d, J= 7.0 Hz, 6H).

Cap-117 to Cap-123

For the preparation of Cap-117 to Cap-123 the Boc amino acids wereobtained from commercially sources and were deprotected by treatmentwith 25% TFA in CH₂Cl₂. After complete reaction as judged by LC-MS thesolvents were removed in vacuo and the corresponding TFA salt of theamino acid was carbamoylated with methyl chloroformate according to theprocedure described for Cap-51.

Cap Structure LC-MS Cap-117

LC-MS: Anal. Calcd. for C₁₂H₁₅NO₄: 237; found: 238 (M + H)⁺. Cap-118

LC-MS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-119

LC-MS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-120

LC-MS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-121

¹H NMR (400 MHz, CDCl₃) δ 4.06-4.16 (m, 1H), 3.63 (s, 3H), 3.43 (s, 1H),2.82 and 2.66 (s, br, 1H), 1.86-2.10 (m, 3H), 1.64-1.76 (m, 2H),1.44-1.53 (m, 1H). Cap-122

¹H NMR profile is similar to that of its stereoisomer, Cap-121. Cap-123

LC-MS: Anal. Calcd. for C₂₇H₂₆N₂O₆: 474; found: 475 (M + H)⁺.

The hydrochloride salt of L-threonine tert-butyl ester was carbamoylatedaccording to the procedure for Cap-51. The crude reaction mixture wasacidified with 1N HCl to pH˜1 and the mixture was extracted with EtOAc(2×50 mL). The combined organic phases were concentrated in vacuo togive a colorless oil which solidified on standing. The aqueous layer wasconcentrated in vacuo and the resulting mixture of product and inorganicsalts was triturated with EtOAc—CH₂Cl₂-MeOH (1:1:0.1) and then theorganic phase concentrated in vacuo to give a colorless oil which wasshown by LC-MS to be the desired product. Both crops were combined togive 0.52 g of a solid. ¹H NMR (400 MHz, CD₃OD) δ 4.60 (m, 1H), 4.04 (d,J=5.0 Hz, 1H), 1.49 (d, J=6.3 Hz, 3H). LC-MS: Anal. Calcd. for C₅H₇NO₄:145. found: 146 (M+H)⁺.

To a suspension of Pd(OH)₂, (20%, 100 mg), aqueous formaldehyde (37% wt,4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added(S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol).The reaction was purged several times with hydrogen and was stirredovernight with an hydrogen balloon room temperature. The reactionmixture was filtered through a pad of diatomaceous earth (CELITE®), andthe volatile component was removed in vacuo. The resulting crudematerial was used as is for the next step. LC-MS: Anal. Calcd. forC₁₁H₂₂N₂O₄: 246. found: 247 (M+H)⁺.

This procedure is a modification of that used to prepare Cap-51. To asuspension of 3-methyl-L-histidine (0.80 g, 4.70 mmol) in THF (10 mL)and H₂O (10 mL) at 0° C. was added NaHCO₃ (0.88 g, 10.5 mmol). Theresulting mixture was treated with ClCO₂Me (0.40 mL, 5.20 mmol) and themixture allowed to stir at 0° C. After stirring for ca. 2 h LC-MS showedno starting material remaining. The reaction was acidified to pH 2 with6 N HCl.

The solvents were removed in vacuo and the residue was suspended in 20mL of 20% MeOH in CH₂Cl₂. The mixture was filtered and concentrated togive a light yellow foam (1.21 g). LC-MS and ¹H NMR showed the materialto be a 9:1 mixture of the methyl ester and the desired product. Thismaterial was taken up in THF (10 mL) and H₂O (10 mL), cooled to 0° C.and LiOH (249.1 mg, 10.4 mmol) was added. After stirring ca. 1 h LC-MSshowed no ester remaining Therefore the mixture was acidified with 6NHCl and the solvents removed in vacuo. LC-MS and ¹H NMR confirm theabsence of the ester. The title compound was obtained as its HCl saltcontaminated with inorganic salts (1.91 g, >100%). The compound was usedas is in subsequent steps without further purification. ¹H NMR (400 MHz,CD₃OD) δ 8.84, (s, 1H), 7.35 (s, 1H), 4.52 (dd, J=5.0, 9.1 Hz, 1H), 3.89(s, 3H), 3.62 (s, 3H), 3.35 (dd, J=4.5, 15.6 Hz, 1H, partially obscuredby solvent), 3.12 (dd, J=9.0, 15.6 Hz, 1H). LC-MS: Anal. Calcd. forC₉H₁₃N₃O₄: 227.09. found: 228.09 (M+H)⁺.

Cap-127 was prepared according to the method for Cap-126 above startingfrom (S)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoic acid (1.11 g,6.56 mmol), NaHCO₃ (1.21 g, 14.4 mmol) and ClCO₂Me (0.56 mL, 7.28 mmol).The title compound was obtained as its HCl salt (1.79 g, >100%)contaminated with inorganic salts. LC-MS and ¹H NMR showed the presenceof ca. 5% of the methyl ester. The crude mixture was used as is withoutfurther purification. ¹H NMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.35 (s,1H), 4.48 (dd, J=5.0, 8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (m,1H), 3.08 (m, 1H); LC-MS: Anal. Calcd. for C₉H₁₃N₃O₄: 227.09. found: 228(M+H)⁺.

Preparation of Cap-128

Step 1. Preparation of (S)-benzyl2-(tert-butoxycarbonylamino)pent-4-ynoate (cj-27b).

To a solution of cj-27a (1.01 g, 4.74 mmol), DMAP (58 mg, 0.475 mmol)and iPr₂NEt (1.7 mL, 9.8 mmol) in CH₂Cl₂ (100 mL) at 0° C. was addedCbz-Cl (0.68 mL, 4.83 mmol). The solution was allowed to stir for 4 h at0° C., washed (1N KHSO₄, brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (TLC 6:1 hex:EtOAc) to give the title compound (1.30 g,91%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (s, 5H), 5.35(d, br, J=8.1 Hz, 1H), 5.23 (d, J=12.2 Hz, 1H), 5.17 (d, J=12.2 Hz, 1H),4.48-4.53 (m, 1H), 2.68-2.81 (m, 2H), 2.00 (t, J=2.5 Hz, 1H), 1.44 (s,9H). LC-MS: Anal. Calcd. for C₁₇H₂₁NO₄: 303. found: 304 (M+H)⁺.

Step 2. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(cj-28).

To a mixture of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate(0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol), CuSO₄-5H₂O(0.022 g, 0.09 mmol) and NaN₃ (0.13 g, 2.1 mmol) in DMF—H₂O (5 mL, 4:1)at rt was added BnBr (0.24 mL, 2.02 mmol) and the mixture was warmed to65° C. After 5 h LC-MS indicated low conversion. A further portion ofNaN₃ (100 mg) was added and heating was continued for 12 h. The reactionwas poured into EtOAc and H₂O and shaken. The layers were separated andthe aqueous layer extracted 3× with EtOAc and the combined organicphases washed (H₂O×3, brine), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash (BIOTAGE®, 40+M 0-5%MeOH in CH₂Cl₂; TLC 3% MeOH in CH₂Cl₂) to afford a light yellow oilwhich solidified on standing (748.3 mg, 104%). The NMR was consistentwith the desired product but suggests the presence of DMF. The materialwas used as is without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ7.84 (s, 1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.07 (s, 2H), 4.25 (m,1H), 3.16 (dd, J=1.0, 5.3 Hz, 1H), 3.06 (dd, J=5.3, 14.7 Hz), 2.96 (dd,J=9.1, 14.7 Hz, 1H), 1.31 (s, 9H). LC-MS: Anal. Calcd. for C₂₄H₂₈N₄O₄:436. found: 437 (M+H)⁺.

Step 3. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(cj-29).

A solution of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(0.52 g, 1.15 mmol) in CH₂Cl₂ was added TFA (4 mL). The mixture wasallowed to stir at room temperature for 2 h. The mixture wasconcentrated in vacuo to give a colorless oil which solidified onstanding. This material was dissolved in THF—H₂O and cooled to 0° C.Solid NaHCO₃ (0.25 g, 3.00 mmol) was added followed by ClCO₂Me (0.25 mL,3.25 mmol). After stirring for 1.5 h the mixture was acidified to pH-2with 6N HCl and then poured into H₂O-EtOAc. The layers were separatedand the aq phase extracted 2× with EtOAc. The combined org layers werewashed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated in vacuoto give a colorless oil (505.8 mg, 111%, NMR suggested the presence ofan unidentified impurity) which solidified while standing on the pump.The material was used as is without further purification. ¹H NMR (400MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.27-7.32 (m,10H), 5.54 (s, 2H), 5.10 (d, J=12.7 Hz, 1H), 5.06 (d, J=12.7 Hz, 1H),4.32-4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, J=5.6, 14.7 Hz, 1H), 2.98(dd, J=9.6, 14.7 Hz, 1H). LC-MS: Anal. Calcd. for C₂₁H₂₂N₄O₄: 394.found: 395 (M+H)⁺.

Step 4. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid(Cap-128).

(S)-Benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(502 mg, 1.11 mmol) was hydrogenated in the presence of Pd—C (82 mg) inMeOH (5 mL) at atmospheric pressure for 12 h. The mixture was filteredthrough diatomaceous earth (CELITE®) and concentrated in vacuo.(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid wasobtained as a colorless gum (266 mg, 111%) which was contaminated withca. 10% of the methyl ester. The material was used as is without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, br, 1H), 7.59 (s,1H), 7.50 (d, J=8.0 Hz, 1H), 4.19-4.24 (m, 1H), 3.49 (s, 3H), 3.12 (dd,J=4.8 Hz, 14.9 Hz, 1H), 2.96 (dd, J=9.9, 15.0 Hz, 1H). LC-MS: Anal.Calcd. for C₇H₁₀N₄O₄: 214. found: 215 (M+H)⁺.

Preparation of Cap-129

Step 1. Preparation of(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid(cj-31).

A suspension of (S)-benzyl 2-oxooxetan-3-ylcarbamate (0.67 g, 3.03mmol), and pyrazole (0.22 g, 3.29 mmol) in CH₃CN (12 mL) was heated at50° C. for 24 h. The mixture was cooled to rt overnight and the solidfiltered to afford(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (330.1mg). The filtrate was concentrated in vacuo and then triturated with asmall amount of CH₃CN (ca. 4 mL) to afford a second crop (43.5 mg).Total yield 370.4 mg (44%). m.p. 165.5-168° C. lit m.p. 168.5-169.5[Vederas et al., J. Am. Chem. Soc., 107:7105 (1985)]. ¹H NMR (400 MHz,CD₃OD) δ 7.51 (d, J=2.0, 1H), 7.48 (s, J=1.5 Hz, 1H), 7.24-7.34 (m, 5H),6.23 m, 1H), 5.05 (d, 12.7H, 1H), 5.03 (d, J=12.7 Hz, 1H), 4.59-4.66 (m,2H), 4.42-4.49 (m, 1H). LC-MS: Anal. Calcd. for C₁₄H₁₅N₃O₄: 289. found:290 (M+H)⁺.

Step 2. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid(Cap-129).

(S)-2-(Benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (0.20g, 0.70 mmol) was hydrogenated in the presence of Pd—C (45 mg) in MeOH(5 mL) at atmospheric pressure for 2 h. The product appeared to beinsoluble in MeOH, therefore the reaction mixture was diluted with 5 mLH₂O and a few drops of 6N HCl. The homogeneous solution was filteredthrough diatomaceous earth (CELITE®), and the MeOH removed in vacuo. Theremaining solution was frozen and lyophyllized to give a yellow foam(188.9 mg). This material was suspended in THF—H₂O (1:1, 10 mL) and thencooled to 0° C. To the cold mixture was added NaHCO₃ (146.0 mg, 1.74mmol) carefully (evolution of CO₂). After gas evolution had ceased (ca.15 min) ClCO₂Me (0.06 mL, 0.78 mmol) was added dropwise. The mixture wasallowed to stir for 2 h and was acidified to pH-2 with 6N HCl and pouredinto EtOAc. The layers were separated and the aqueous phase extractedwith EtOAC (×5). The combined organic layers were washed (brine), dried(Na₂SO₄), filtered, and concentrated to give the title compound as acolorless solid (117.8 mg, 79%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s,1H), 7.63 (d, J=2.6 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.5 Hz,1H), 6.19 (app t, J=2.0 Hz, 1H), 4.47 (dd, J=3.0, 12.9 Hz, 1H),4.29-4.41 (m, 2H), 3.48 (s, 3H). LC-MS: Anal. Calcd. for C₈H₁₁N₃O₄: 213.found: 214 (M+H)⁺.

Cap-130 was prepared by acylation of commercially available(R)-phenylglycine analogous to the procedure given in: Calmes, M. etal., Tetrahedron, 43(10):2285 (1987).

Step a: Dimethylcarbamoyl chloride (0.92 mL, 10 mmol) was added slowlyto a solution of (S)-benzyl 2-amino-3-methylbutanoate hydrochloride(2.44 g; 10 mmol) and Hunig's base (3.67 mL, 21 mmol) in THF (50 mL).The resulting white suspension was stirred at room temperature overnight(16 hours) and concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The resulting yellow oil was purified by flashchromatography, eluting with ethyl acetate:hexanes (1:1). Collectedfractions were concentrated under vacuum providing 2.35 g (85%) of clearoil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (d, J=6.95 Hz, 3H), 0.89 (d,J=6.59 Hz, 3H), 1.98-2.15 (m, 1H), 2.80 (s, 6H), 5.01-5.09 (m, J=12.44Hz, 1H), 5.13 (d, J=12.44 Hz, 1H), 6.22 (d, J=8.05 Hz, 1H), 7.26-7.42(m, 5H). LC (Cond. 1): RT=1.76 min; MS: Anal. Calcd. for [M+H]⁺C₁₆H₂₂N₂O₃: 279.17. found 279.03.

Step b: To an MeOH (50 mL) solution of the intermediate prepared above(2.35 g; 8.45 mmol) was added Pd/C (10%; 200 mg) and the resulting blacksuspension was flushed with N₂ (3×) and placed under 1 atm of H₂. Themixture was stirred at room temperature overnight and filtered though amicrofiber filter to remove the catalyst. The resulting clear solutionwas then concentrated under reduced pressure to obtain 1.43 g (89%) ofCap-131 as a white foam, which was used without further purification. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 0.87 (d, J=4.27 Hz, 3H), 0.88 (d, J=3.97Hz, 3H), 1.93-2.11 (m, 1H), 2.80 (s, 6H), 3.90 (dd, J=8.39, 6.87 Hz,1H), 5.93 (d, J=8.54 Hz, 1H), 12.36 (s, 1H). LC (Cond. 1): RT=0.33 min;MS: Anal. Calcd. for [M+H]⁺ C₈H₁₇N₂O₃: 189.12. found 189.04.

Cap-132 was prepared from (S)-benzyl 2-aminopropanoate hydrochlorideaccording to the method described for Cap-131. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.27 (d, J=7.32 Hz, 3H), 2.80 (s, 6H), 4.06 (qt, 1H), 6.36 (d,J=7.32 Hz, 1H), 12.27 (s, 1H). LC (Cond. 1): RT=0.15 min; MS: Anal.Calcd. for [M+H]⁺ C₆H₁₃N₂O₃: 161.09. found 161.00.

Cap-133 was prepared from (S)-tert-butyl 2-amino-3-methylbutanoatehydrochloride and 2-fluoroethyl chloroformate according to the methoddescribed for Cap-47. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87 (t, J=6.71Hz, 6H), 1.97-2.10 (m, 1H), 3.83 (dd, J=8.39, 5.95 Hz, 1H), 4.14-4.18(m, 1H), 4.20-4.25 (m, 1H), 4.50-4.54 (m, 1H), 4.59-4.65 (m, 1H), 7.51(d, J=8.54 Hz, 1H), 12.54 (s, 1H).

Cap-134 was prepared from (S)-diethyl alanine and methyl chloroformateaccording to the method described for Cap-51. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.72-0.89 (m, 6H), 1.15-1.38 (m, 4H), 1.54-1.66 (m, 1H), 3.46-3.63(m, 3H), 4.09 (dd, J=8.85, 5.19 Hz, 1H), 7.24 (d, J=8.85 Hz, 1H), 12.55(s, 1H). LC (Cond. 2): RT=0.66 min; LC-MS: Anal. Calcd. for [M+H]⁺C₉H₁₈NO₄: 204.12. found 204.02.

A solution of D-2-amino-(4-fluorophenyl)acetic acid (338 mg, 2.00 mmol),1N HCl in diethylether (2.0 mL, 2.0 mmol) and formalin (37%, 1 mL) inmethanol (5 mL) was subjected to balloon hydrogenation over 10%palladium on carbon (60 mg) for 16 h at 25° C. The mixture was thenfiltered through CELITE® to afford the HCl salt of Cap-135 as a whitefoam (316 mg, 80%). ¹H NMR (300 MHz, MeOH-d₄) δ 7.59 (dd, J=8.80, 5.10Hz, 2H), 7.29 (t, J=8.6 Hz, 2H), 5.17 (s, 1H), 3.05 (v br s, 3H), 2.63(v br s, 3H); R_(t)=0.19 min (Cond.-MS-W5); 95% homogenity index; LRMS:Anal. Calcd. for [M+H]⁺ C₁₀H₁₃FNO₂: 198.09. found: 198.10.

To a cooled (−50° C.) suspension of 1-benzyl-1H-imidazole (1.58 g, 10.0mmol) in anhydrous diethyl ether (50 mL) under nitrogen was addedn-butyl lithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) dropwise. Afterbeing stirred for 20 min at −50° C., dry carbon dioxide (passed throughDrierite) was bubbled into the reaction mixture for 10 min before it wasallowed to warm up to 25° C. The heavy precipitate which formed onaddition of carbon dioxide to the reaction mixture was filtered to yielda hygroscopic, white solid which was taken up in water (7 mL), acidifiedto pH=3, cooled, and induced to crystallize with scratching. Filtrationof this precipitate gave a white solid which was suspended in methanol,treated with 1N HCl/diethyl ether (4 mL) and concentrated in vacuo.Lyophilization of the residue from water (5 mL) afforded the HCl salt ofCap-136 as a white solid (817 mg, 40%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.94(d, J=1.5 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.50-7.31 (m, 5H), 5.77 (s,2H); R_(t)=0.51 min (Cond.-MS-W5); 95% homogenity index; LRMS: Anal.Calc. for [M+H]⁺ C₁₁H₁₂N₂O₂: 203.08. found: 203.11.

A suspension of 1-chloro-3-cyanoisoquinoline (188 mg, 1.00 mmol;prepared according to the procedure in WO 2003/099274) (188 mg, 1.00mmol), cesium fluoride (303.8 mg, 2.00 mmol),bis(tri-tert-butylphosphine)palladium dichloride (10 mg, 0.02 mmol) and2-(tributylstannyl)furan (378 μL, 1.20 mmol) in anhydrous dioxane (10mL) under nitrogen was heated at 80° C. for 16 h before it was cooled to25° C. and treated with saturated, aqueous potassium fluoride solutionwith vigorous stirring for 1 h. The mixture was partitioned betweenethyl acetate and water and the organic phase was separated, washed withbrine, dried over Na₂SO₄, filtered and concentrated. Purification of theresidue on silica gel (elution with 0% to 30% ethyl acetate/hexanes)afforded Cap-137, step a as a white solid which was used as is (230 mg,105%). R_(t)=1.95 min (Cond.-MS-W2); 90% homogeneity index; LRMS: Anal.Calc. for [M+H]⁺ C₁₄H₈N₂O: 221.07. found: 221.12.

To a suspension of Cap-137, step a (110 mg, 0.50 mmol) and sodiumperiodate (438 mg, 2.05 mmol) in carbon tetrachloride (1 mL),acetonitrile (1 mL) and water (1.5 mL) was added ruthenium trichloridehydrate (2 mg, 0.011 mmol). The mixture was stirred at 25° C. for 2 hand then partitioned between dichloromethane and water. The aqueouslayer was separated, extracted twice more with dichloromethane and thecombined dichloromethane extracts were dried over Na₂SO₄, filtered andconcentrated. Trituration of the residue with hexanes afforded Cap-137(55 mg, 55%) as a grayish-colored solid. R_(t)=1.10 min (Cond.-MS-W2);90% homogeneity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₁H₈N₂O₂: 200.08.found: 200.08.

Cap-138 to Cap-158

Synthetic Strategy. Method A.

To a stirred suspension of 5-hydroxisoquinoline (prepared according tothe procedure in WO 2003/099274) (2.0 g, 13.8 mmol) andtriphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) wasadded dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5mmol) portionwise. The mixture was stirred at room temperature for 20 hbefore it was diluted with ethyl acetate and washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was preabsorbed ontosilica gel and purified (elution with 40% ethyl acetate/hexanes) toafford Cap-138, step a as a light yellow solid (1.00 g, 45%). ¹H NMR(CDCl₃, 500 MHz) δ 9.19 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 7.99 (d, J=6.0Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); R_(t)=0.66min (Cond. D2); 95% homogeneity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₀H₁₀NO: 160.08. found 160.10.

To a stirred solution of Cap-138, step a (2.34 g, 14.7 mmol) inanhydrous dichloromethane (50 mL) at room temperature was addedmeta-chloroperbenzoic acid (77%, 3.42 g, 19.8 mmol) in one portion.After being stirred for 20 h, powdered potassium carbonate (2.0 g) wasadded and the mixture was stirred for 1 h at room temperature before itwas filtered and concentrated to afford Cap-138, step b as a pale,yellow solid which was sufficiently pure to carry forward (2.15 g,83.3%). ¹H NMR (CDCl₃, 400 MHz) δ 8.73 (d, J=1.5 Hz, 1H), 8.11 (dd,J=7.3, 1.7 Hz, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.28(d, J=8.3 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.00 (s, 3H); R_(t)=0.92 min,(Cond.-D1); 90% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₀H₁₀NO₂: 176.07. found: 176.0.

To a stirred solution of Cap-138, step b (0.70 g, 4.00 mmol) andtriethylamine (1.1 mL, 8.00 mmol) in dry acetonitrile (20 mL) at roomtemperature under nitrogen was added trimethylsilylcyanide (1.60 mL,12.00 mmol). The mixture was heated at 75° C. for 20 h before it wascooled to room temperature, diluted with ethyl acetate and washed withsaturated sodium bicarbonate solution and brine prior to drying overNa₂SO₄ and solvent concentration. The residue was flash chromatographedon silica gel (elution with 5% ethyl acetate/hexanes) to 25% ethylacetate/hexanes to afford Cap-138, step c (498.7 mg) as a white,crystalline solid along with 223 mg of additional Cap-138, step crecovered from the filtrate. ¹H NMR (CDCl₃, 500 MHz) δ 8.63 (d, J=5.5Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.69 (t, J=8.0Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 4.04 (s, 3H); R_(t)=1.75 min,(Cond.-D1); 90% homogeneity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₁H₉N₂O: 185.07. found: 185.10.

Cap-138, step c (0.45 g, 2.44 mmol) was treated with 5N sodium hydroxidesolution (10 mL) and the resulting suspension was heated at 85° C. for 4h, cooled to 25° C., diluted with dichloromethane and acidified with 1Nhydrochloric acid. The organic phase was separated, washed with brine,dried over Na₂SO₄, concentrated to ¼volume and filtered to affordCap-138 as a yellow solid (0.44 g, 88.9%). ¹H NMR (DMSO-d₆, 400 MHz) δ13.6 (br s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.06(d, J=8.8 Hz, 1H), 7.71-7.67 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.02 (s,3H); R_(t)=0.70 min (Cond.-D1); 95% homogenity index; LC-MS: Anal. Calc.for [M+H]⁺ C₁₁H₁₀NO₃: 204.07. found: 204.05.

Synthetic Strategy. Method B (derived from Tetrahedron Letters, 42:6707(2001)).

To a thick-walled, screw-top vial containing an argon-degassedsuspension of 1-chloro-6-methoxyisoquinoline (1.2 g, 6.2 mmol; preparedaccording to the procedure in WO 2003/099274), potassium cyanide (0.40g, 6.2 mmol), 1,5-bis(diphenylphosphino)pentane (0.27 g, 0.62 mmol) andpalladium (II) acetate (70 mg, 0.31 mmol) in anhydrous toluene (6 mL)was added N,N,N′,N′-tetramethylethylenediamine (0.29 mL, 2.48 mmol). Thevial was sealed, heated at 150° C. for 22 h and then allowed to cool to25° C. The reaction mixture was diluted with ethyl acetate, washed withwater and brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel eluting with 5% ethyl acetate/hexanesto 25% ethyl acetate/hexanes to afford Cap-139, step a as a white solid(669.7 mg). ¹H NMR (CDCl₃, 500 MHz) δ 8.54 (d, J=6.0 Hz, 1H), 8.22 (d,J=9.0 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.41-7.39 (m, 1H), 7.13 (d, J=2.0Hz, 1H), 3.98 (s, 3H); R_(t)=1.66 min (Cond.-D1); 90% homogenity index;LC-MS: Anal. Calc. for [M+H]⁺ C₁₁H₉N₂O: 185.07. found: 185.20.

Cap-139 was prepared from the basic hydrolysis of Cap-139, step a with5N NaOH according to the procedure described for Cap-138. ¹H NMR (400MHz, DMSO-d₆) δ 13.63 (v br s, 1H), 8.60 (d, J=9.3 Hz, 1H), 8.45 (d,J=5.6 Hz, 1H), 7.95 (d, J=5.9 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.44 (dd,J=9.3, 2.5 Hz, 1H), 3.95 (s, 3H); R_(t)=0.64 min (Cond.-D1); 90%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₁H₁₀NO₃: 204.07.found: 204.05.

To a vigorously-stirred mixture of 1,3-dichloro-5-ethoxyisoquinoline(482 mg, 2.00 mmol; prepared according to the procedure in WO2005/051410), palladium (II) acetate (9 mg, 0.04 mmol), sodium carbonate(223 mg, 2.10 mmol) and 1,5-bis(diphenylphosphino)pentane (35 mg, 0.08mmol) in dry dimethylacetamide (2 mL) at 25° C. under nitrogen was addedN,N,N′,N′-tetramethylethylenediamine (60 mL, 0.40 mmol). After 10 min,the mixture was heated to 150° C., and then a stock solution of acetonecyanohydrin (prepared from 457 μL of acetone cyanohydrin in 4.34 mL DMA)was added in 1 mL portions over 18 h using a syringe pump. The mixturewas then partitioned between ethyl acetate and water and the organiclayer was separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel eluting with 10%ethyl acetate/hexanes to 40% ethyl acetate/hexanes to afford Cap-140,step a as a yellow solid (160 mg, 34%). R_(t)=2.46 min (Cond.-MS-W2);90% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₂H₉C1N₂O: 233.05.found: 233.08.

Cap-140 was prepared by the acid hydrolysis of Cap-140, step a with 12NHCl as described in the procedure for the preparation of Cap-141,described below. R_(t)=2.24 min (Cond.-MS-W2); 90% homogenity index;LC-MS: Anal. Calc. for [M+H]⁺ C₁₂H₁₁ClNO₃: 252.04. found: 252.02.

Cap-141, step a was prepared from 1-bromo-3-fluoroisoquinoline (preparedfrom 3-amino-1-bromoisoquinoline using the procedure outlined in J. Med.Chem., 13:613 (1970)) as described in the procedure for the preparationof Cap-140, step a (vide supra). ¹H NMR (500 MHz, CDCl₃) δ 8.35 (d,J=8.5 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.63 Hz, 1H),7.77-7.73 (m, 1H), 7.55 (s, 1H); R_(t)=1.60 min (Cond.-D1); 90%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₀H₆FN₂: 173.05. found:172.99.

Cap-141, step a (83 mg, 0.48 mmol) was treated with 12N HCl (3 mL) andthe resulting slurry was heated at 80° C. for 16 h before it was cooledto room temperature and diluted with water (3 mL). The mixture wasstirred for 10 min and then filtered to afford Cap-141 as an off-whitesolid (44.1 mg, 47.8%). The filtrate was diluted with dichloromethaneand washed with brine, dried over Na₂SO₄, and concentrated to affordadditional Cap-141 which was sufficiently pure to be carried forwarddirectly (29.30 mg, 31.8%). ¹H NMR (DMSO-d₆, 500 MHz) δ 14.0 (br s, 1H),8.59-8.57 (m, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.88-7.85 (m, 2H), 7.74-7.71(m, 1H); R_(t)=1.33 min (Cond.-D1); 90% homogenity index; LC-MS: Anal.Calc. for [M+H]⁺ C₁₀H₇FNO₂: 192.05. found: 191.97.

Cap-142, step a was prepared from 4-bromoisoquinoline N-oxide asdescribed in the two-step procedure for the preparation of Cap-138,steps b and c. R_(t)=1.45 min (Cond.-MS-W1); 90% homogenity index;LC-MS: Anal. Calc. for [M+H]⁺ C₁₀H₆BrN₂: 232.97. found: 233.00.

To an argon-degassed suspension of Cap-142, step a (116 mg, 0.50 mmol),potassium phosphate tribasic (170 mg, 0.80 mmol), palladium (II) acetate(3.4 mg, 0.015 mmol) and 2-(dicyclohexylphosphino)biphenyl (11 mg, 0.03mmol) in anhydrous toluene (1 mL) was added morpholine (61 μL, 0.70mmol). The mixture was heated at 100° C. for 16 h, cooled to 25° C. andfiltered through diatomaceous earth (CELITE®). Purification of theresidue on silica gel, eluting with 10% to 70% ethyl acetate/hexanesafforded Cap-142, step b (38 mg, 32%) as a yellow solid, which wascarried forward directly. R_(t)=1.26 min (Cond.-MS-W1); 90% homogenityindex; LC-MS: Anal. Calc. for [M+H]⁺ C₁₄H₁₄N₃O: 240.11. found: 240.13.

Cap-142 was prepared from Cap-142, step b with 5N sodium hydroxide asdescribed in the procedure for Cap-138. R_(t)=0.72 min (Cond.-MS-W1);90% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₄H₁₅N₂O₃: 259.11.found: 259.08.

To a stirred solution of 3-amino-1-bromoisoquinoline (444 mg, 2.00 mmol)in anhydrous dimethylformamide (10 mL) was added sodium hydride (60%,unwashed, 96 mg, 2.4 mmol) in one portion. The mixture was stirred at25° C. for 5 min before 2-bromoethyl ether (90%, 250 μL, 2.00 mmol) wasadded. The mixture was stirred further at 25° C. for 5 h and at 75° C.for 72 h before it was cooled to 25° C., quenched with saturatedammonium chloride solution and diluted with ethyl acetate. The organiclayer was separated, washed with water and brine, dried over Na₂SO₄,filtered and concentrated. Purification of the residue on silica geleluting with 0% to 70% ethyl acetate/hexanes afforded Cap-143, step a asa yellow solid (180 mg, 31%). R_(t)=1.75 min (Cond.-MS-W1); 90%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₃H₁₄BrN₂O: 293.03.found: 293.04.

To a cold (−60° C.) solution of Cap-143, step a (154 mg, 0.527 mmol) inanhydrous tetrahydrofuran (5 mL) was added a solution of n-butyllithiumin hexanes (2.5 M, 0.25 mL, 0.633 mmol). After 10 min, dry carbondioxide was bubbled into the reaction mixture for 10 min before it wasquenched with 1N HCl and allowed to warm to 25° C. The mixture was thenextracted with dichloromethane (3×30 mL) and the combined organicextracts were concentrated in vacuo. Purification of the residue by areverse phase HPLC (MeOH/water/TFA) afforded Cap-143 (16 mg, 12%).R_(t)=1.10 min (Cond.-MS-W1); 90% homogenity index; LC-MS: Anal. Calc.for [M+H]⁺ C₁₄H₁₅N₂O₃: 259.11. found: 259.08.

1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in smallportions to a cold (0° C.) solution of fuming nitric acid (10 mL) andconcentrated sulfuric acid (10 mL). The mixture was stirred at 0° C. for0.5 h before it was gradually warmed to 25° C. where it stirred for 16h. The mixture was then poured into a beaker containing chopped ice andwater and the resulting suspension was stirred for 1 h at 0° C. beforeit was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellowsolid which was used directly. R_(t)=2.01 min. (Cond.-D1); 95%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₉H₅Cl₂N₂O₂: 242.97.found: 242.92.

Cap-144, step a (0.30 g, 1.23 mmol) was taken up in methanol (60 mL) andtreated with platinum oxide (30 mg), and the suspension was subjected toParr hydrogenation at 7 psi H₂ for 1.5 h. Then formalin (5 mL) andadditional platinum oxide (30 mg) were added, and the suspension wasresubjected to Parr hydrogenation at 45 psi H₂ for 13 h. It was thensuction-filtered through diatomaceous earth (CELITE®) and concentrateddown to ¼volume. Suction-filtration of the ensuing precipitate affordedthe title compound as a yellow solid which was flash chromatographed onsilica gel eluting with 5% ethyl acetate in hexanes to 25% ethyl acetatein hexanes to afford Cap-144, step b (231 mg, 78%) as a pale yellowsolid. R_(t)=2.36 min (Cond.-D1); 95% homogenity index; ¹H NMR (400 MHz,CDCl₃) δ 8.02 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.57-7.53 (m, 1H), 7.30(d, J=7.3 Hz, 1H), 2.88 (s, 6H); LC-MS: Anal. Calc. for [M+H]⁺C₁₁H₁₁Cl₂N₂: 241.03. found: 241.02. HRMS: Anal. Calc. for [M+H]⁺C₁₁H₁₁Cl₂N₂: 241.0299. found: 241.0296.

Cap-144, step c was prepared from Cap-144, step b according to theprocedure described for the preparation of Cap-139, step a. R_(t)=2.19min (Cond.-D1); 95% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₂H₁₁ClN₃: 232.06. found: 232.03. HRMS: Anal. Calc. for [M+H]⁺C₁₂H₁₁ClN₃: 232.0642. found: 232.0631.

Cap-144 was prepared according to the procedure described for Cap-141.R_(t)=2.36 min (Cond.-D1); 90%; LC-MS: Anal. Calc. for [M+H]⁺C₁₂H₁₂ClN₂O₂: 238.01. found: 238.09.

Cap-145 to Cap-162

Cap-145 to Cap-162 were prepared from the appropriate1-chloroisoquinolines according to the procedure described for thepreparation of Cap-138 (Method A) or Cap-139 (Method B) unless notedotherwise as outlined below.

R_(t) (LC-Cond.); % homogeneity Cap # Cap Method Hydrolysis index; MSdata Cap-145

B 12N HCl 1.14 min (Cond.- MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇ClNO₂: 208.02; found: 208.00. Cap-146

A 5N NaOH 1.40 min (Cond.- D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 204.06. Cap-147

B 5N NaOH 0.87 min (Cond.- D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 204.05. Cap-148

A 5N NaOH 0.70 min (Cond.- D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 204.05. Cap-149

A 5N NaOH 0.70 min (Cond.- D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 204.05. Cap-150

A 12N HCl 0.26 min (Cond.- D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 204.04. Cap-151 3-chloro-5-methoxyisoquinoline 1-carboxylic acid

B 12N HCl 1.78 min (Cond.- D1); 90%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₉ClNO₃: 238.03; found: 238.09. Cap-152

B 12N HCl 1.65 min (Cond.- D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₉ClNO₃: 238.00; found: 238.09. Cap-153

A 6N HCl 1.18 min (Cond.- MS-W1); 95%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇BrNO₂: 251.97; found: 251.95. Cap-154

B 5N NaOH 0.28 min (Cond.- MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇FNO₂: 192.05; found: 192.03. Cap-155

B 5N NaOH 0.59 min (Cond.- MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇ClNO₂: 208.02; found: 208.00. Cap-156

B 5N NaOH 0.60 min (Cond.- MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇ClNO₂: 208.02; found: 208.03. Cap-157

B 12N HCl 1.49 min (Cond.- D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₀H₁₇ClNO: 208.02; found: 208.00. Cap-158

B 5N NaOH 0.69 min (Cond.- MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇ClNO₂: 208.02; found: 208.01. Cap-159

B 5N NaOH 0.41 min (Cond.- MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇FNO₂: 192.05; found: 192.03. Cap-160

B 5N NaOH 0.30 min (Cond.- MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇FNO₂: 192.05; found: 192.03. Cap-161

— — 0.70 min (Cond. D1); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₂H₁₃N₂O₂: 217.10; found: 217.06. Cap-162

— — 0.65 min (Cond.- M3); 95%; LC- MS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 203.94.

To a solution of 2-ketobutyric acid (1.0 g, 9.8 mmol) in diethylether(25 ml) was added phenylmagnesium bromide (22 ml, 1M in THF) dropwise.The reaction was stirred at ˜25° C. under nitrogen for 17.5 h. Thereaction was acidified with 1N HCl and the product was extracted withethyl acetate (3×100 ml). The combined organic layer was washed withwater followed by brine and dried over MgSO₄. After concentration invacuo, a white solid was obtained. The solid was recrystallized fromhexanes/ethyl acetate to afford Cap-163 as white needles (883.5 mg). ¹HNMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.71 (br s, 1H), 7.54-7.52 (m, 2H),7.34-7.31 (m, 2H), 7.26-7.23 (m, 1H), 5.52-5.39 (br s, 1H), 2.11 (m,1H), 1.88 (m, 1H), 0.79 (app t, J=7.4 Hz, 3H).

A mixture of 2-amino-2-phenylbutyric acid (1.5 g, 8.4 mmol),formaldehyde (14 mL, 37% in water), 1N HCl (10 mL) and 10% Pd/C (0.5 mg)in MeOH (40 mL) was exposed to H₂ at 50 psi in a Parr bottle for 42 h.The reaction was filtered over CELITE® and concentrated in vacuo, theresidue was taken up in MeOH (36 mL) and the product was purified with areverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA salt of Cap-164 as awhite solid (1.7 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz) 7.54-7.47 (m,5H), 2.63 (m, 1H), 2.55 (s, 6H), 2.31 (m, 1H), 0.95 (app t, J=7.3 Hz,3H).

To a mixture of 2-amino-2-indanecarboxylic acid (258.6 mg, 1.46 mmol)and formic acid (0.6 ml, 15.9 mmol) in 1,2-dichloroethane (7 ml) wasadded formaldehyde (0.6 ml, 37% in water). The mixture was stirred at˜25° C. for 15 min then heated at 70° C. for 8 h. The volatile componentwas removed in vacuo, and the residue was dissolved in DMF (14 mL) andpurified by a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA saltof Cap-165 as a viscous oil (120.2 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500MHz): 7.29-7.21 (m, 4H), 3.61 (d, J=17.4 Hz, 2H), 3.50 (d, J=17.4 Hz,2H), 2.75 (s, 6H). LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₆NO₂: 206.12.found: 206.07.

Cap-166a and Cap-166b were prepared from(1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (2HBr) according tothe method described for the synthesis of Cap-7a and Cap-7b, with theexception that the benzyl ester intermediate was separated using asemi-prep Chrialcel OJ column, 20×250 mm, 10 μm eluting with 85:15heptane/ethanol mixture at 10 mL/min elution rate for 25 min. Cap-166b:¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 7.45 (d, J=7.3 Hz, 2H), 7.27-7.19(m, 3H), 4.09 (s, 1H), 3.34 (app br s, 1H), 3.16 (app br s, 1H), 2.83(d, J=10.1 Hz, 1H), 2.71 (m, 2H), 2.46 (m, 1H), 2.27 (s, 3H), 1.77 (d,J=9.8 Hz, 1H), 1.63 (d, J=9.8 Hz, 1H). LC-MS: Anal. Calcd. for [M+H]⁺C₁₄H₁₉N₂O₂: 247.14. found: 247.11.

A solution of racemic Boc-1,3-dihydro-2H-isoindole carboxylic acid (1.0g, 3.8 mmol) in 20% TFA/CH₂Cl₂ was stirred at ˜25° C. for 4 h. All thevolatile component was removed in vacuo. A mixture of the resultantcrude material, formaldehyde (15 mL, 37% in water), 1N HCl (10 mL) and10% Pd/C (10 mg) in MeOH was exposed to H₂ (40 PSI) in a Parr bottle for23 h. The reaction mixture was filtered over CELITE® and concentrated invacuo to afford Cap-167 as a yellow foam (873.5 mg). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 500 MHz) 7.59-7.38 (m, 4H), 5.59 (s, 1H), 4.84 (d, J=14 Hz,1H), 4.50 (d, J=14.1 Hz, 1H), 3.07 (s, 3H). LC-MS: Anal. Calcd. for[M+H]⁺ C₁₀H₁₂NO₂: 178.09. found: 178.65.

Racemic Cap-168 was prepared from racemic Boc-aminoindane-1-carboxylicacid according to the procedure described for the preparation ofCap-167. The crude material was employed as such.

A mixture of 2-amino-2-phenylpropanoic acid hydrochloride (5.0 g, 2.5mmol), formaldehyde (15 ml, 37% in water), 1N HCl (15 ml), and 10% Pd/C(1.32 g) in MeOH (60 mL) was placed in a Parr bottle and shaken underhydrogen (55 PSI) for 4 days. The reaction mixture was filtered overCELITE® and concentrated in vacuo. The residue was taken up in MeOH andpurified by reverse phase prep-HPLC (MeOH/water/TFA) to afford the TFAsalt of Cap-169 as a viscous semi-solid (2.1 g). ¹H NMR (CDCl₃, δ=7.26ppm, 500 MHz): 7.58-7.52 (m, 2H), 7.39-7.33 (m, 3H), 2.86 (br s, 3H),2.47 (br s, 3H), 1.93 (s, 3H). LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂:194.12. found: 194.12.

(S)-2-(Methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid

To (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid (505 mg; 3.18mmol; obtained from Astatech) in water (15 ml) was added sodiumcarbonate (673 mg; 6.35 mmol), and the resultant mixture was cooled to0° C. and then methyl chloroformate (0.26 ml; 3.33 mmol) was addeddropwise over 5 minutes. The reaction was allowed to stir for 18 hourswhile allowing the bath to thaw to ambient temperature. The reactionmixture was then partitioned between 1N HCl and ethyl acetate. Theorganic layer was removed and the aqueous layer was further extractedwith 2 additional portions of ethyl acetate. The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford Cap-170 a colorless residue. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.65 (1H, br s), 7.44 (1H, d, J=8.24 Hz), 3.77-3.95(3H, m), 3.54 (3H, s), 3.11-3.26 (2H, m), 1.82-1.95 (1H, m), 1.41-1.55(2H, m), 1.21-1.39 (2H, m); LC-MS: Anal. Calcd. for [M+H]⁺ C₉H₁₆NO₅:218.1. found 218.1.

A solution of methyl2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (200 mg, 0.721mmol; Il Farmaco (2001), 56, 609-613) in ethyl acetate (7 ml) and CH₂Cl₂(4.00 ml) was degassed by bubbling nitrogen for 10 min. Dimethyldicarbonate (0.116 ml, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) werethen added, the reaction mixture was fitted with a hydrogen balloon andallowed to stir at ambient temperature overnight at which time TLC (95:5CH₂Cl₂/MeOH: visualized with stain made from 1 g Ce(NH₄)₂SO₄, 6 gammonium molybdate, 6 ml sulfuric acid, and 100 ml water) indicatedcomplete conversion. The reaction was filtered through CELITE® andconcentrated. The residue was purified via BIOTAGE® (load withdichloromethane on 25 samplet; elute on 25S column with dichloromethanefor 3CV then 0 to 5% MeOH/dichloromethane over 250 ml then hold at 5%MeOH/dichloromethane for 250 ml; 9 ml fractions). Collected fractionscontaining desired material and concentrated to 120 mg (81%) of methyl2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil. ¹HNMR (500 MHz, chloroform-d) δ ppm 3.29-3.40 (m, J=6.71 Hz, 1H) 3.70 (s,3H) 3.74 (s, 3H) 4.55 (t, J=6.41 Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m,2H) 5.31 (br s, 1H). LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₁₄NO₅: 204.2.found 204.0.

To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxidemonohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowedto stir overnight at ambient temperature. TLC (1:1 EA/Hex; Hanessianstain [1 g Ce(NH₄)₂SO₄, 6 g ammonium molybdate, 6 ml sulfuric acid, and100 ml water]) indicated ˜10% starting material remaining Added anadditional 3 mg LiOH and allowed to stir overnight at which time TLCshowed no starting material remaining Concentrated in vacuo and placedon high vac overnight providing 55 mg lithium2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless solid. ¹HNMR (500 MHz, MeOD) δ ppm 3.39-3.47 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.93Hz, 1H) 4.64 (t, J=6.26 Hz, 1H) 4.68 (t, J=7.02 Hz, 1H) 4.73 (d, J=7.63Hz, 2H).

The following diazotization step was adapted from Barton, A. et al., J.C. S. Perkin Trans I, 159-164 (1982): A solution of NaNO₂ (166 mg, 2.4mmol) in water (0.6 mL) was added slowly to a stirred, cold (0° C.)solution of methyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186 mg,1.0 mmol), CuSO₄.5H₂O (330 mg, 1.32 mmol), NaCl (260 mg, 4.45 mmol) andH₂SO₄ (5.5 mL) in water (7.5 mL). The mixture was stirred at 0° C. for45 min and allowed to warm up to room temperature where it stirredfurther for 1 h before CuCl (118 mg) was added. This mixture was stirredfurther at room temperature for 16 h before it was diluted with brineand extracted with ether twice. The organic layers were combined, driedover MgSO₄ and concentrated to give methyl2-chloro-5-ethylthiazole-4-carboxylate (i.e., Cap-172, step a) (175 mg,85%) as an orange oil (80% pure) which was used directly in the nextreaction. R_(t)=1.99 min (Cond.-MD1); LC-MS: Anal. Calcd. for [M+H]⁺C₇H₉ClNO₂S: 206.01. found: 206.05.

Cap-172

To a solution of methyl 2-chloro-5-ethylthiazole-4-carboxylate (175 mg)in THF/H₂O/MeOH (20 mL/3 mL/12 mL) was added LiOH (305 mg, 12.76 mmol).The mixture was stirred at room temperature overnight before it wasconcentrated down and neutralized with 1N HCl in ether (25 mL). Theresidue was extracted twice with ethyl acetate and the organic layerswere combined, dried over MgSO₄ and evaporated to yield Cap-172 (60 mg,74%) as a red solid which was used without further purification. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.03-13.42 (1H, m), 3.16 (2H, q, J=7.4 Hz),1.23 (3H, t, J=7.5 Hz). R_(t)=1.78 min (Cond.-MD1); LC-MS: Anal. Calcd.for [M+H]⁺ C₆H₇ClNO₂S: 191.99. found: 191.99.

The following diazotization step was adapted from Barton, A. et al.,J.C.S. Perkin Trans I, 159-164 (1982): A solution of NaNO₂ (150 mg, 2.17mmol) in water (1.0 mL) was added dropwise to a stirred, cold (0° C.)solution of methyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186 mg,1.0 mmol) in 50% H₃PO₂ (3.2 mL). The mixture was stirred at 0° C. for 1h and allowed to warm up to room temperature where it stirred furtherfor 2 h. After recooling to 0° C., the mixture was treated slowly with asolution of NaOH (85 mg) in water (10 mL). The mixture was then dilutedwith saturated NaHCO₃ solution and extracted twice with ether. Theorganic layers were combined, dried over MgSO₄ and concentrated to givemethyl 5-ethylthiazole-4-carboxylate (i.e., Cap-173, step a) (134 mg,78%) as an orange oil (85% pure) which was used directly in the nextreaction. R_(t)=1.58 min (Cond.-MD1); LC-MS: Anal. Calcd. for [M+H]⁺C₇H₁₀NO₂S: 172.05. found: 172.05.

Cap-173

To a solution of methyl 5-ethylthiazole-4-carboxylate (134 mg) inTHF/H₂O/MeOH (18 mL/2.7 mL/11 mL) was added LiOH (281 mg, 11.74 mmol).The mixture was stirred at room temperature overnight before it wasconcentrated down and neutralized with 1N HCl in ether (25 mL). Theresidue was extracted twice with ethyl acetate and the organic layerswere combined, dried over MgSO₄ and evaporated to yield Cap-173 (90 mg,73%) as an orange solid which was used without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 12.74-13.04 (1H, m), 3.20 (2H, q, J=7.3Hz), 1.25 (3H, t, J=7.5 Hz). R_(t)=1.27 min (Cond.-MD1); LC-MS: Anal.Calcd. for [M+H]⁺ C₆H₈NO₂S: 158.03. found: 158.04.

Triflic anhydride (5.0 g, 18.0 mmol) was added dropwise to a cold (0°C.) solution of methyl 3-hydroxypicolinate (2.5 g, 16.3 mmol) and TEA(2.5 mL, 18.0 mmol) in CH₂Cl₂ (80 mL). The mixture was stirred at 0° C.for 1 h before it was allowed to warm up to room temperature where itstirred for an additional 1 h. The mixture was then quenched withsaturated NaHCO₃ solution (40 mL) and the organic layer was separated,washed with brine, dried over MgSO₄ and concentrated to give methyl3-(trifluoromethylsulfonyloxy)picolinate (i.e., Cap-174, step a) (3.38g, 73%) as a dark brown oil (>95% pure) which was used directly withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.72-8.79 (1H, m),7.71 (1H, d, J=1.5 Hz), 7.58-7.65 (1H, m), 4.04 (3H, s). R_(t)=1.93 min(Cond.-MD1); LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₇F₃NO₅S: 286.00. found:286.08.

Cap-174

To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (570mg, 2.0 mmol) in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol),tributyl(vinyl)stannane (761 mg, 2.4 mmol) andbis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). Themixture was heated at 100° C. overnight before a saturated solution ofKF (20 mL) was added to the reaction mixture at room temperature. Thismixture was stirred for 4 h before it was filtered through CELITE® andthe pad of CELITE® was washed with ethyl acetate. The aqueous phase ofthe filtrate was then separated and concentrated down in vacuo. Theresidue was treated with 4N HCl in dioxanes (5 mL) and the resultingmixture was extracted with methanol, filtered and evaporated to affordCap-174 (260 mg) as a green solid which was slightly contaminated withinorganic salts but was used without further purification. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.21 (1H, d, J=3.7 Hz), 7.81-7.90 (1H, m), 7.09 (1H,dd, J=7.7, 4.8 Hz), 6.98 (1H, dd, J=17.9, 11.3 Hz), 5.74 (1H, dd,J=17.9, 1.5 Hz), 5.20 (1H, d, J=11.0 Hz). R_(t)=0.39 min (Cond.-MD1);LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₈NO₂: 150.06. found: 150.07.

To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e.,Cap-174, step a) (570 mg, 2.0 mmol), an intermediate in the preparationof Cap-174, in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol),tributyl(vinyl)stannane (761 mg, 2.4 mmol) andbis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). Themixture was heated at 100° C. for 4 h before the solvent was removed invacuo. The residue was taken up in acetonitrile (50 mL) and hexanes (50mL) and the resulting mixture was washed twice with hexanes. Theacetonitrile layer was then separated, filtered through CELITE®, andevaporated. Purification of the residue by flash chromatography on aHorizon instrument (gradient elution with 25% ethyl acetate in hexanesto 65% ethyl acetate in hexanes) afforded methyl 3-vinylpicolinate(i.e., Cap-175, step a) (130 mg, 40%) as a yellow oil. ¹H NMR (300 MHz,CDCl₃) δ ppm 8.60 (1H, dd, J=4.6, 1.7 Hz), 7.94 (1H, d, J=7.7 Hz),7.33-7.51 (2H, m), 5.72 (1H, d, J=17.2 Hz), 5.47 (1H, d, J=11.0 Hz),3.99 (3H, s). R_(t)=1.29 min (Cond.-MD1); LC-MS: Anal. Calcd. for [M+H]⁺C₉H₁₀NO₂: 164.07. found: 164.06.

Palladium on carbon (10%, 25 mg) was added to a solution of methyl3-vinylpicolinate (120 mg, 0.74 mmol) in ethanol (10 mL). The suspensionwas stirred at room temperature under an atmosphere of hydrogen for 1 hbefore it was filtered through CELITE® and the pad of CELITE® was washedwith methanol. The filtrate was concentrated down to dryness to yieldmethyl 3-ethylpicolinate (i.e., Cap-175, step b) which was takendirectly into the next reaction. R_(t)=1.15 min (Cond.-MD1); LC-MS:Anal. Calcd. for [M+H]⁺ C₉H₁₂NO₂: 166.09. found: 166.09.

Cap-175

To a solution of methyl 3-ethylpicolinate in THF/H₂O/MeOH (5 mL/0.75mL/3 mL) was added LiOH (35 mg, 1.47 mmol). The mixture was stirred atroom temperature for 2 d before additional LiOH (80 mg) was added. Afteran additional 24 h at room temperature, the mixture was filtered and thesolvent was removed in vacuo. The residue was then treated with 4N HClin dioxanes (5 mL) and the resulting suspension was concentrated down todryness to yield Cap-175 as a yellow solid which was used withoutfurther purification. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.47 (1H, dd,J=4.8, 1.5 Hz), 7.82-7.89 (1H, m), 7.53 (1H, dd, J=7.7, 4.8 Hz), 2.82(2H, q, J=7.3 Hz), 1.17 (3H, t, J=7.5 Hz). R_(t)=0.36 min (Cond.-MD1);LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₁₀NO₂: 152.07. found: 152.10.

(S)-2-(4,4-Difluorocyclohexyl)-2-(methoxycarbonylamino)acetic acid

A solution of 1,4-dioxaspiro[4.5]decan-8-one (15 g, 96 mmol) in EtOAc(150 mL) was added to a solution of methyl2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (21.21 g, 64.0mmol) in 1,1,3,3-tetramethylguanidine (10.45 mL, 83 mmol) and EtOAc (150mL). The resulting solution was the stirred at ambient temperature for72 h and then it was diluted with EtOAc (25 mL). The organic layer waswashed with 1N HCl (75 mL), H₂O (100 mL) and brine (100 mL), dried(MgSO₄), filtered and concentrated. The residue was purified viaBIOTAGE® (5% to 25% EtOAc/Hexanes; 300 g column). The combined fractionscontaining the product were then concentrated under vacuum and theresidue was re-crystallized from hexanes/EtOAc to give white crystalsthat corresponded to methyl2-(benzyloxycarbonylamino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate(6.2 g)¹H NMR (400 MHz, CDCl₃-d) δ ppm 7.30-7.44 (5H, m), 6.02 (1H, br.s.), 5.15 (2H, s), 3.97 (4H, s), 3.76 (3H, br. s.), 2.84-2.92 (2H, m),2.47 (2H, t, J=6.40 Hz), 1.74-1.83 (4H, m). LC (Cond. OL1): R_(t)=2.89min. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₉H₂₃NNaO₆: 745.21. found: 745.47.

Ester Cap-176, step b was prepared from alkene Cap-176, step a accordingto the method of Burk, M. J. et al. (J. Am. Chem. Soc., 117:9375-9376(1995)) and references therein): A 500 mL high-pressure bottle wascharged with alkene Cap-176, step a (3.5 g, 9.68 mmol) in degassed MeOH(200 mL) under a blanket of N₂. The solution was then charged with(−)-1,2-Bis((2S,5S)-2,5-dimethylphospholano)ethane(cyclooctadiene)rhodium (I) tetrafluoroborate (0.108 g, 0.194 mmol) and the resultingmixture was flushed with N₂ (3×) and charged with H₂ (3×). The solutionwas shaken vigorously under 70 psi of H₂ at ambient temperature for 72h. The solvent was removed under reduced pressure and the remainingresidue was taken up in EtOAc. The brownish solution was then filteredthrough a plug of Silica Gel and eluted with EtOAc. The solvent wasconcentrated under vacuum to afford a clear oil corresponding to esterCap-176, step b (3.4 g). ¹H NMR (500 MHz, CDCl₃-d) δ ppm 7.28-7.43 (5H,m), 5.32 (1H, d, J=9.16 Hz), 5.06-5.16 (2H, m), 4.37 (1H, dd, J=9.00,5.04 Hz), 3.92 (4H, t, J=3.05 Hz), 3.75 (3H, s), 1.64-1.92 (4H, m),1.37-1.60 (5H, m). LC (Cond. OL1): R_(t)=1.95 min. LC-MS: Anal. Calcd.for [M+H]⁺ C₁₉H₂₆NO₆: 364.18. found: 364.27.

Ester Cap-176, step b (4.78 g, 13.15 mmol) was dissolved in THF (15 mL)followed by sequential addition of water (10 mL), glacial acetic acid(26.4 mL, 460 mmol) and dichloroacetic acid (5.44 mL, 65.8 mmol). Theresulting mixture was stirred for 72 h at ambient temperature, and thereaction was quenched by slow addition of solid Na₂CO₃ with vigorousstirring until the release of gas was no longer visible. Crude productwas extracted into 10% ethyl acetate-dichloromethane and the organiclayers were combined, dried (MgSO₄) filtered and concentrated. Theresulting residue was purified via BIOTAGE® (0 to 30% EtOAc/Hex; 25 gcolumn) to afford ketone Cap-176, step c (3.86 g) as a clear oil. ¹H NMR(400 MHz, CDCl₃-d) δ ppm 7.28-7.41 (5H, m), 5.55 (1H, d, J=8.28 Hz),5.09 (2H, s), 4.46 (1H, dd, J=8.16, 5.14 Hz), 3.74 (3H, s), 2.18-2.46(5H, m), 1.96-2.06 (1H, m), 1.90 (1H, ddd, J=12.99, 5.96, 2.89 Hz),1.44-1.68 (2H, m, J=12.36, 12.36, 12.36, 12.36, 4.77 Hz). LC (Cond.OL1): R_(t)=1.66 min. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₇H₂₁NNaO₅:342.13. found: 342.10.

DEOXO-FLUOR® (3.13 mL, 16.97 mmol) was added to a solution of ketoneCap-176, step c (2.71 g, 8.49 mmol) in CH₂Cl₂ (50 mL) followed byaddition of a catalytic amount of EtOH (0.149 mL, 2.55 mmol). Theresulting yellowish solution was stirred at rt overnight. The reactionwas quenched by addition of sat. aq. NaHCO₃ (25 mL) and the mixture wasextracted with EtOAc (3×75 mL)). The combined organic layers were dried(MgSO₄), filtered and dried to give a yellowish oil. The residue waspurified via BIOTAGE® chromatography (2% to 15% EtOAc/Hex; 90 g column)and a white solid corresponding to the difluoro amino acid difluorideCap-176, step d (1.5 g) was recovered. ¹H NMR (400 MHz, CDCl₃-d) δ ppm7.29-7.46 (5H, m), 5.34 (1H, d, J=8.28 Hz), 5.12 (2H, s), 4.41 (1H, dd,J=8.66, 4.89 Hz), 3.77 (3H, s), 2.06-2.20 (2H, m), 1.83-1.98 (1H, m),1.60-1.81 (4H, m), 1.38-1.55 (2H, m). ¹⁹F NMR (376 MHz, CDCl₃-d) δ ppm−92.15 (1F, d, J=237.55 Hz), −102.44 (1F, d, J=235.82 Hz). LC (Cond.OL1): R_(t)=1.66 min. LC-MS: Anal. Calcd. for [2M+Na]⁺ C₃₄H₄₂F₄N₂NaO₈:705.28. found: 705.18.

Difluoride Cap-176, step d (4 g, 11.72 mmol) was dissolved in MeOH (120mL) and charged with Pd/C (1.247 g, 1.172 mmol). The suspension wasflushed with N₂ (3×) and the reaction mixture was placed under 1 atm ofH₂ (balloon). The mixture was stirred at ambient temperature for 48 h.The suspension was then filtered though a plug of CELITE® andconcentrated under vacuum to give an oil that corresponded to amino acidCap-176, step e (2.04 g) and that was used without further purification.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.62 (3H, s), 3.20 (1H, d, J=5.77 Hz),1.91-2.09 (2H, m), 1.50-1.88 (7H, m), 1.20-1.45 (2H, m). ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −89.39 (1F, d, J=232.35 Hz), −100.07 (1F, d,J=232.35 Hz). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 175.51 (1C, s), 124.10(1C, t, J=241.21, 238.90 Hz), 57.74 (1C, s), 51.39 (1C, s), 39.23 (1C,br. s.), 32.02-33.83 (2C, m), 25.36 (1C, d, J=10.02 Hz), 23.74 (1C, d,J=9.25 Hz). LC (Cond. OL2): R_(t)=0.95 min. LC-MS: Anal. Calcd. for[2M+H]⁺ C₁₈H₃₁F₄N₂O₂: 415.22. found: 415.40.

Methyl chloroformate (1.495 mL, 19.30 mmol) was added to a solution ofamino acid Cap-176, step e (2 g, 9.65 mmol) and DIEA (6.74 mL, 38.6mmol) in CH₂Cl₂ (100 mL). The resulting solution was stirred at rt for 3h and volatiles were removed under reduced pressure. The residue waspurified via BIOTAGE® (0% to 20% EtOAc/Hex; 90 g column). A clear oilthat solidified upon standing under vacuum and corresponding tocarbamate Cap-176, step f (2.22 g) was recovered. ¹H NMR (500 MHz,CDCl₃-d) δ ppm 5.27 (1H, d, J=8.55 Hz), 4.39 (1H, dd, J=8.85, 4.88 Hz),3.77 (3H, s), 3.70 (3H, s), 2.07-2.20 (2H, m), 1.84-1.96 (1H, m),1.64-1.82 (4H, m), 1.39-1.51 (2H, m). ¹⁹F NMR (471 MHz, CDCl₃-d) δ ppm−92.55 (1F, d, J=237.13 Hz), −102.93 (1F, d, J=237.12 Hz). ¹³C NMR (126MHz, CDCl₃-d) δ ppm 171.97 (1C, s), 156.69 (1C, s), 119.77-125.59 (1C,m), 57.24 (1C, br. s.), 52.48 (1C, br. s.), 52.43 (1C, s), 39.15 (1C,s), 32.50-33.48 (2C, m), 25.30 (1C, d, J=9.60 Hz), 24.03 (1C, d, J=9.60Hz). LC (Cond. OL1): R_(t)=1.49 min. LC-MS: Anal. Calcd. for [M+Na]⁺C₁₁H₁₇F₂NNaO₄: 288.10. found: 288.03.

(S)-2-(4,4-Difluorocyclohexyl)-2-(methoxycarbonylamino)acetic acid

A solution of LiOH (0.379 g, 15.83 mmol) in water (25 mL) was added to asolution of carbamate Cap-176, step f (2.1 g, 7.92 mmol) in THF (75 mL)and the resulting mixture was stirred at ambient temperature for 4 h.THF was removed under vacuum and the remaining aqueous phase wasacidified with 1N HCl solution (2 mL) and then extracted with EtOAc(2×50 mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated to give a white foam corresponding to Cap-176 (1.92 g). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.73 (1H, s), 7.50 (1H, d, J=8.78 Hz),3.97 (1H, dd, J=8.53, 6.02 Hz), 3.54 (3H, s), 1.92-2.08 (2H, m),1.57-1.90 (5H, m), 1.34-1.48 (1H, m), 1.27 (1H, qd, J=12.72, 3.26 Hz).¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −89.62 (1F, d, J=232.35 Hz), −99.93(1F, d, J=232.35 Hz). LC (Cond. OL2): R_(t)=0.76 min. LC-MS: Anal.Calcd. for [M−H]⁺ C₁₀H₁₄F₂NO₄: 250.09. found: 250.10.

1,1,3,3-Tetramethylguanidine (0.985 mL, 7.85 mmol) was added to astirred solution of methyl2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (2.0 g, 6.0mmol) in EtOAc (40 mL) and the mixture was stirred at rt under N₂ for 10min. Then dihydro-2H-pyran-3(4H)-one [23462-75-1] (0.604 g, 6.04 mmol)was added and the mixture was stirred at rt for 16 h. The reactionmixture was then cooled in freezer for 10 min and neutralized with aq.citric acid (1.5 g in 20 mL water). The two phases were partitioned andthe organic layer was washed with 0.25 N aq. HCl and brine, and thendried (MgSO₄) and concentrated to a colorless oil. The crude materialwas purified by flash silica chromatography (loading solvent: DCM,eluted with EtOAc/Hexanes, gradient from 20% to 30% EtOAc) to yield twoisomeric products: The first eluted product was (Z)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate (490mg) (white solid), and the second was (E)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate (433mg) (white solid). LC-MS retention time 1.398 min (for Z-isomer) and1.378 min (for E-isomer); m/z 304.08 (for Z-isomer) and 304.16 (forE-isomer) (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) (for Z-isomer) δ ppm 7.30-7.44 (m, 5H), 6.18 (br. s., 1H),5.10-5.17 (m, 2H), 4.22 (s, 2H), 3.78 (br. s., 3H), 2.93-3.02 (m, 2H),1.80 (dt, J=11.7, 5.8 Hz, 2H), 1.62 (s, 2H). ¹H NMR (400 MHz,chloroform-d) (for E-isomer) δ ppm 7.31-7.44 (m, 5H), 6.12 (br. s., 1H),5.13-5.17 (m, 2H), 4.64 (br. s., 2H), 3.70-3.82 (m, 5H), 2.49 (t, J=6.5Hz, 2H), 1.80 (br. s., 2H). (Note: the absolute regiochemistry wasdetermined by ¹H NMR shifts and coupling constants).

(−)-1,2-Bis((2S,5S)-2,5-dimethylphospholano)ethane(cyclooctadiene)-rhodium(I)tetrafluoroborate(28.2 mg, 0.051 mmol) was added to a stirred solution of (Z)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate (310mg, 1.015 mmol) in MeOH (10 mL) and the mixture was vacuum flushed withN₂, followed by H₂, and then the reaction was stirred under H₂ (60 psi)at rt for 2 d. The reaction mixture was concentrated and the residue waspurified by flash silica chromatography (loading solvent: DCM, elutedwith 20% EtOAc in hexanes) to yield (S)-methyl2-(benzyloxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (204mg) as clear colorless oil. LC-MS retention time 1.437 min; m/z 307.89(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.30-7.46 (m, 5H), 5.32 (d, J=8.8 Hz, 1H), 5.12 (s,2H), 4.36 (dd, J=8.9, 5.6 Hz, 1H), 3.84-3.98 (m, 2H), 3.77 (s, 3H),3.28-3.37 (m, 1H), 3.23 (dd, J=11.3, 10.5 Hz, 1H), 2.04-2.16 (m, 1H),1.61-1.75 (m, 3H), 1.31-1.43 (m, 1H).

The other stereoisomer ((E)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate) (360mg, 1.18 mmol) was reduced in a similar manner to yield (S)-methyl2-(benzyloxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate (214mg) as clear colorless oil. LC-MS retention time 1.437 min; m/z 308.03(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.30-7.44 (m, 5H), 5.31 (d, J=9.0 Hz, 1H), 5.12 (s,2H), 4.31 (dd, J=8.7, 6.9 Hz, 1H), 3.80-3.90 (m, 2H), 3.77 (s, 3H), 3.37(td, J=10.8, 3.5 Hz, 1H), 3.28 (dd, J=11.3, 9.8 Hz, 1H), 1.97-2.10 (m,1H), 1.81 (d, J=11.5 Hz, 1H), 1.61-1.72 (m, 2H), 1.33-1.46 (m, 1H).

10% Pd/C (69.3 mg, 0.065 mmol) was added to a solution of (S)-methyl2-(benzyloxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (200mg, 0.651 mmol) and dimethyl dicarbonate [4525-33-1] (0.104 mL, 0.976mmol) in MeOH (10 mL). The reaction mixture was vacuum flushed with N₂,followed by H₂, and then the reaction was stirred under H₂ (55 psi) atrt for 5 h. The reaction mixture was filtered through CELITE®/silica padand the filtrate was concentrated to a colorless oil. The crude oil waspurified by flash silica chromatography (loading solvent: DCM, elutedwith 30% EtOAc in hexanes) to yield product (S)-methyl2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (132mg) as colorless oil. LC-MS retention time 0.92 min; m/z 231.97 (MH+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min,a hold time of 1 min, and an analysis time of 4 min where Solvent A was5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95%MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (400 MHz, chloroform-d) δppm 5.24 (d, J=8.5 Hz, 1H), 4.34 (dd, J=8.9, 5.6 Hz, 1H), 3.84-3.97 (m,2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.29-3.38 (m, 1H), 3.23 (dd, J=11.2,10.4 Hz, 1H), 2.03-2.14 (m, 1H), 1.56-1.75 (m, 3H), 1.32-1.43 (m, 1H).

Another diastereomer ((S)-methyl2-(benzyloxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate) wastransformed in a similar manner to yield (S)-methyl2-(methoxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate asclear colorless oil. LC-MS retention time 0.99 min; m/z 231.90 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min,a hold time of 1 min, and an analysis time of 4 min where Solvent A was5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95%MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (400 MHz, chloroform-d) δppm 5.25 (d, J=8.0 Hz, 1H), 4.29 (dd, J=8.4, 7.2 Hz, 1H), 3.82-3.90 (m,2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.37 (td, J=10.8, 3.3 Hz, 1H), 3.28 (t,J=10.5 Hz, 1H), 1.96-2.08 (m, 1H), 1.81 (dd, J=12.9, 1.6 Hz, 1H),1.56-1.72 (m, 2H), 1.33-1.46 (m, 1H).

To a solution of (S)-methyl2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (126mg, 0.545 mmol) in THF (4 mL) stirring at rt was added a solution of 1MLiOH (1.090 mL, 1.090 mmol) in water. The reaction was stirred at rt for3 h, neutralized with 1M HCl (1.1 mL) and extracted with EtOAc (3×10mL). The organics were dried, filtered and concentrated to yield(S)-2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetic acid(Cap-177a) (125 mg) as a clear colorless oil. LC-MS retention time 0.44min; m/z 218.00 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 5.28 (d, J=8.8 Hz, 1H), 4.38 (dd, J=8.7, 5.6 Hz,1H), 3.96-4.04 (m, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.71 (s, 3H), 3.33-3.41(m, 1H), 3.24-3.32 (m, 1H), 2.10-2.24 (m, 1H), 1.74-1.83 (m, 1H),1.63-1.71 (m, 2H), 1.35-1.49 (m, 1H).

Another diastereomer ((S)-methyl2-(methoxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate) wastransformed in a similar manner to yield(S)-2-(methoxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetic acid(Cap-177b) as clear colorless oil. LC-MS retention time 0.41 min; m/z217.93 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 6.18 (br. s., 1H), 5.39 (d, J=8.5 Hz, 1H), 4.27-4.37(m, 1H), 3.82-3.96 (m, 2H), 3.72 (s, 3H), 3.42 (td, J=10.8, 3.3 Hz, 1H),3.35 (t, J=10.4 Hz, 1H), 2.01-2.18 (m, 1H), 1.90 (d, J=11.8 Hz, 1H),1.59-1.76 (m, 2H), 1.40-1.54 (m, 1H).

To a solution of (2S,3S,4S)-2-methyl-3,4-dihydro-2H-pyran-3,4-diyldiacetate (5 g, 23.34 mmol) in 20 mL of MeOH in a hydrogenation tank wasadded Pd/C (150 mg, 0.141 mmol). The resulting mixture was hydrogenatedat 40 psi on Parr Shaker for 1 hour. The mixture was then filtered andthe filtrate was concentrated to afford Cap-178, step a (5.0 g) as aclear oil, which solidified while standing. ¹H NMR (500 MHz, CDCl₃) δppm 4.85-4.94 (1H, m), 4.69 (1H, t, J=9.46 Hz), 3.88-3.94 (1H, m), 3.44(1H, td, J=12.21, 1.83 Hz), 3.36 (1H, dq, J=9.42, 6.12 Hz), 2.03-2.08(1H, m), 2.02 (3H, s), 2.00 (3H, s), 1.70-1.80 (1H, m), 1.16 (3H, d,J=6.10 Hz).

To a solution of Cap-178, step a (5.0 g, 23 mmol) in 50 mL of MeOH wasadded several drops of sodium methoxide. After stirring at roomtemperature for 30 min, sodium methoxide (0.1 mL, 23.12 mmol) was addedand the solution was stirred at room temperature overnight. The solventwas then removed under vacuum. The residue was diluted with benzene andconcentrated to afford the corresponding diol as a yellow solid. Thesolid was dissolved in 50 mL of pyridine and to this solution at −35° C.was added benzoyl chloride (2.95 mL, 25.4 mmol) dropwise. The resultingmixture was stirred at −35° C. for 1 hour then at room temperatureovernight. The mixture was diluted with Et₂O and washed with water. Theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere dried with MgSO₄ and concentrated. The crude product was purifiedby flash chromatography (silica gel, 5%-15% EtOAc/Hex) to affordCap-178, step b (4.5 g) as clear oil which slowly crystallized uponprolonged standing. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₃H₁₆NaO₄ 259.09.found 259.0; ¹H NMR (500 MHz, CDCl₃) δ ppm 8.02-8.07 (2H, m), 7.55-7.61(1H, m), 7.45 (2H, t, J=7.78 Hz), 5.01 (1H, ddd, J=11.44, 8.70, 5.49Hz), 3.98 (1H, ddd, J=11.90, 4.88, 1.53 Hz), 3.54 (1H, td, J=12.36, 2.14Hz), 3.41 (1H, t, J=9.00 Hz), 3.31-3.38 (1H, m), 2.13-2.19 (1H, m),1.83-1.94 (1H, m), 1.36 (3H, d, J=5.80 Hz).

To a mixture of NaH (1.143 g, 28.6 mmol) (60% in mineral oil) in 6 mL ofCS₂ was added Cap-178, step b (4.5 g, 19 mmol) in 40 mL of CS₂ dropwiseover 15 min. The resulting mixture was stirred at room temperature for30 min. The mixture turned light orange with some solid. MeI (14.29 mL,229 mmol) was then added dropwise over 20 min. The mixture was thenstirred at room temperature overnight. The reaction was carefullyquenched with saturated NH₄Cl solution. The mixture was extracted withEtOAc (3×). The combined organic layers were dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 6% EtOAc/Hex) to afford Cap-178, step c (3.13 g) as clearoil. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₅H₁₈NaO₄S₂ 349.05. found 349.11;¹H NMR (500 MHz, CDCl₃) δ ppm 7.94-8.00 (2H, m), 7.50-7.58 (1H, m), 7.41(2H, t, J=7.78 Hz), 5.96 (1H, t, J=9.46 Hz), 5.28 (1H, ddd, J=11.37,9.38, 5.49 Hz), 4.02 (1H, ddd, J=11.98, 4.96, 1.68 Hz), 3.54-3.68 (2H,m), 2.48 (3H, s), 2.31 (1H, dd), 1.88-1.99 (1H, m), 1.28 (3H, d).

To a mixture of Cap-178, step c (3.13 g, 9.59 mmol) and AIBN (120 mg,0.731 mmol) in 40 mL of benzene at 80° C. was added tri-n-butyltinhydride (10.24 mL, 38.4 mmol). The resulting mixture was stirred atreflux temperature for 20 min then cooled to room temperature. Themixture was diluted with diethyl ether and 100 mL of KF (10 g) aqueoussolution was added and the mixture was stirred vigorously for 30 min.The two layers were then separated and the aqueous phase was extractedwith EtOAc (2×). The organic layer was dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, deactivated with 3% Et₃N in Hexanes and flushed with 3%Et₃N in Hexanes to remove tributyltin derivative and then eluted with15% EtOAc/Hex) to afford Cap-178, step d (1.9 g) as clear oil. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.98-8.07 (2H, m), 7.52-7.58 (1H, m), 7.43 (2H,t, J=7.63 Hz), 5.08-5.17 (1H, m), 4.06 (1H, ddd, J=11.90, 4.88, 1.53Hz), 3.50-3.59 (2H, m), 2.08-2.14 (1H, m), 1.99-2.06 (1H, m), 1.69-1.80(1H, m), 1.41-1.49 (1H, m), 1.24 (3H, d, J=6.10 Hz).

To a mixture of Cap-178, step d (1.9 g, 8.63 mmol) in 10 mL of MeOH wasadded sodium methoxide (2 mL, 4.00 mmol) (2 M in methanol). Theresulting mixture was stirred at room temperature for 5 hours. Thesolvent was removed under vacuum. The mixture was neutralized withsaturated NH₄Cl solution and extracted with EtOAc (3×). The organiclayers were dried with MgSO₄ and concentrated to afford Cap-178, step e(0.8 g) as clear oil. The product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.01 (1H, ddd,J=11.80, 5.02, 1.76 Hz), 3.73-3.83 (1H, m), 3.36-3.46 (2H, m), 1.92-2.00(1H, m), 1.88 (1H, m), 1.43-1.56 (1H, m), 1.23 (3H, d), 1.15-1.29 (1H,m).

Tosyl-C1 (2.63 g, 13.77 mmol) was added to a solution of Cap-178, step e(0.8 g, 6.89 mmol) and pyridine (2.23 mL, 27.5 mmol) in 100 mL ofCH₂Cl₂. The resulting mixture was stirred at room temperature for 3days. 10 mL of water was then added into the reaction mixture and themixture was stirred at room temperature for an hour. The two layers wereseparated and the organic phase was washed with water and 1 N HCl aq.solution. The organic phase was dried with MgSO₄ and concentrated toafford Cap-178, step f (1.75 g) as a light yellow solid. The product wasused in the next step without further purification. Anal. Calcd. for[M+H]⁺ C₁₃H₁₉O₄S 271.10. found 270.90; ¹H NMR (500 MHz, CDCl₃) δ ppm7.79 (2H, d, J=8.24 Hz), 7.34 (2H, d, J=7.93 Hz), 4.53-4.62 (1H, m),3.94 (1H, ddd, J=12.13, 4.96, 1.83 Hz), 3.29-3.41 (2H, m), 2.45 (3H, s),1.90-1.97 (1H, m), 1.79-1.85 (1H, m), 1.64-1.75 (1H, m), 1.38-1.48 (1H,m), 1.17 (3H, d, J=6.10 Hz).

To a microwave tube was placed ethyl 2-(diphenylmethyleneamino)acetate(1.6 g, 5.92 mmol) and Cap-178, step f (1.6 g, 5.92 mmol). 10 mL oftoluene was added. The tube was sealed and LiHMDS (7.1 mL, 7.10 mmol) (1N in toluene) was added dropwise under N₂. The resulting dark brownsolution was heated at 100° C. under microwave radiation for 6 hours. Tothe mixture was then added water and the mixture was extracted withEtOAc (3×). The combined organic layers were washed with brine, driedwith MgSO₄ and concentrated to afford a diastereomeric mixture of Cap-3,step g (3.1 g) as an orange oil. The crude mixture was submitted to thenext step without separation. LC-MS: Anal. Calcd. for [M+H]⁺ C₂₃H₂₈NO₃366.21. found 366.3.

To a solution of the diastereomeric mixture of ethyl Cap-178, step g in20 mL of THF was added HCl (30 ml, 60.0 mmol) (2 N aqueous). Theresulting mixture was stirred at room temperature for 1 hour. Themixture was extracted with EtOAc and the aqueous layer was concentratedto afford an HCl salt of Cap-178, step h (1.9 g) as an orange oil. Thesalt was used in the next step without further purification. LC-MS:Anal. Calcd. for [M+H]⁺ C₁₀H₂₀NO₃ 202.14. found 202.1.

A solution of 1.9 g Cap-178, step h (HCl salt), DiPEA (4.19 mL, 24.0mmol) and methyl chloroformate (1.24 mL, 16.0 mmol) in 20 mL of CH₂Cl₂was stirred at room temperature for 1 hour. The mixture was diluted withCH₂Cl₂ and washed with water. The organic layer was dried with Na₂SO₄and concentrated. The crude product was purified by flash chromatography(silica gel, 0-20% EtOAc/Hex) to afford Cap-178, step i (1.1 g) as ayellow oil. Anal. Calcd. for [M+Na]⁺ C₁₂H₂₁NNaO₅ 282.13. found 282.14;¹H NMR (400 MHz, CDCl₃) δ ppm 5.16 (1H, br. s.), 4.43-4.58 (1H, m),4.17-4.28 (2H, m), 3.89-4.03 (1H, m), 3.72-3.78 (2H, m), 3.67-3.72 (3H,m), 2.07-2.19 (1H, m), 1.35-1.77 (4H, m), 1.30 (3H, td, J=7.09, 2.89Hz), 1.19 (3H, d, J=6.53 Hz).

To a mixture of Cap-178, step i (1.1 g, 4.2 mmol) in 5 mL of THF and 2mL of water was added LiOH (6.36 mL, 12.7 mmol) (2 N aq.). The resultingmixture was stirred at room temperature overnight. The mixture was thenneutralized with 1 N HCl aq. and extracted with EtOAc (3×). The combinedorganic layers were dried with MgSO₄ and concentrated to afford Cap-178,step j (0.8 g) as a clear oil. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₈NO₅232.12. found 232.1; ¹H NMR (400 MHz, CDCl₃) δ ppm 5.20 (1H, d, J=8.28Hz), 4.54 (1H, t, J=8.16 Hz), 3.95-4.10 (1H, m), 3.66-3.85 (5H, m),2.15-2.29 (1H, m), 1.41-1.85 (4H, m), 1.23 (3H, dd, J=6.53, 1.76 Hz).

To a solution of Cap-178, step j (240 mg, 1.04 mmol),(S)-1-phenylethanol (0.141 mL, 1.142 mmol) and EDC (219 mg, 1.14 mmol)in 10 mL of CH₂Cl₂ was added DMAP (13.95 mg, 0.114 mmol). The resultingsolution was stirred at room temperature overnight and the solvent wasremoved under vacuum. The residue was taken up into EtOAc, washed withwater, dried with MgSO₄ and concentrated. The crude product was purifiedby chromatography (silica gel, 0-15% EtOAc/Hexanes) to afford Cap-178,step k as a mixture of two diastereomers. The mixture was separated bychiral HPLC (CHIRALPAK® AS column, 21×250 mm, 10 um) eluting with 90%0.1% diethylamine/Heptane-10% EtOH at 15 mL/min to afford Cap-178, stepk stereoisomer 1 (eluted first) and Cap-178, step k stereoisomer 2(eluted second) as white solids. The stereochemistry of the isomers wasnot assigned.

Cap-178, step k stereoisomer 1 (130 mg): LC-MS: Anal. Calcd. for [M+Na]⁺C₁₈H₂₅NNaO₅ 358.16. found 358.16; ¹H NMR (500 MHz, CDCl₃) δ ppm7.28-7.38 (5H, m), 5.94 (1H, q, J=6.71 Hz), 5.12 (1H, d, J=9.16 Hz),4.55 (1H, t, J=9.00 Hz), 3.72-3.81 (1H, m), 3.67 (3H, s), 3.60-3.70 (2H,m), 1.98-2.08 (1H, m), 1.59 (3H, d, J=6.71 Hz), 1.38-1.47 (2H, m), 1.30(2H, t, J=5.34 Hz), 0.93 (3H, d, J=6.41 Hz).

Cap-178, Stereoisomer 1

To a solution of Cap-178, step k stereoisomer 1((S)-2-(methoxycarbonylamino)-2-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)aceticacid) (150 mg, 0.447 mmol) in 10 mL of EtOH was added Pd/C (20 mg, 0.188mmol) and the mixture was hydrogenated on Parr shaker at 40 psiovernight. The mixture was then filtered and the filtrate wasconcentrated to afford Cap-178, stereoisomer 1 (100 mg) as a stickywhite solid. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₈NO₅ 232.12. found232.1; ¹H NMR (500 MHz, CDCl₃) δ ppm 5.14-5.27 (1H, m), 4.51 (1H, t,J=8.39 Hz), 3.90-4.07 (1H, m), 3.60-3.83 (5H, m), 2.06-2.27 (1H, m),1.45-1.77 (4H, m), 1.21 (3H, d, J=6.41 Hz).

2,6-Dimethyl-4H-pyran-4-one (10 g, 81 mmol) was dissolved in ethanol(125 mL) and Pd/C (1 g, 0.94 mmol) was added. The mixture washydrogenated in a Parr shaker under H₂ (0.325 g, 161 mmol) (70 psi) atroom temperature for 12 hrs. The catalyst was filtered through a pad ofCELITE® and washed with ethanol. The filtrate was concentrated in vacuumand he residue was purified via BIOTAGE® (2% to 25% EtOAc/Hex; 160 gcolumn). Two fractions of clear oils were isolated. The first elutingone corresponded to (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (1.8g) while the second one corresponded to Cap-179, step a (1.8 g).

(2R,6S)-2,6-Dimethyldihydro-2H-pyran-4(3H)-one data: ¹H NMR (500 MHz,CDCl₃) δ ppm 3.69 (2H, ddd, J=11.29, 5.95, 2.29 Hz), 2.24-2.36 (2H, m),2.08-2.23 (2H, m), 1.18-1.34 (6H, m); ¹³C NMR (126 MHz, CDCl₃) δ ppm206.96 (1C, br. s.), 72.69 (2C, s), 48.70 (2C, s), 21.72 (2C, s).

Cap-179, step a data: ¹H NMR (500 MHz, CDCl₃) δ ppm 3.69-3.78 (1H, m),3.36-3.47 (2H, m), 2.10 (1H, br. s.), 1.88 (2H, dd, J=12.05, 4.73 Hz),1.19 (6H, d, J=6.10 Hz), 1.10 (2H, q, J=10.70 Hz); ¹³C NMR (126 MHz,CDCl₃) δ ppm 71.44 (2C, s), 67.92 (1C, s), 42.59 (2C, s), 21.71 (2C, s).

DEAD (2.311 mL, 14.59 mmol) was added drop wise to a solution ofCap-179, step a (0.38 g, 2.92 mmol), 4-nitrobenzoic acid (2.195 g, 13.14mmol) and Ph₃P (3.83 g, 14.59 mmol) in benzene (25 mL). Heat evolutionwas detected and the resulting amber solution was stirred at ambienttemperature for 6 h. Solvent was removed under reduced pressure and theresidue was purified via BIOTAGE® (0 to 15% EtOAc/Hex; 80 g column). Awhite solid corresponding to Cap-179, step b (0.77 g) was isolated.LC-MS: Anal. Calcd. for [M]⁺ C₁₄H₁₇NO₅: 279.11. found 279.12. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.27-8.32 (2H, m), 8.20-8.24 (2H, m), 5.45 (1H,quin, J=2.82 Hz), 3.92 (2H, dqd, J=11.90, 6.10, 6.10, 6.10, 1.53 Hz),1.91 (2H, dd, J=14.80, 2.29 Hz), 1.57 (3H, dt, J=14.65, 3.05 Hz), 1.22(6H, d, J=6.10 Hz).

A solution LiOH (0.330 g, 13.8 mmol) in water (8 mL) was added to asolution of Cap-179, step b (0.77 g, 2.76 mmol) in THF (30 mL) and theresulting mixture was stirred at ambient temperature for 16 h. THF wasremoved under reduced pressure and the aqueous layer was diluted withmore water (20 mL) and extracted with EtOAc (3×15 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated undervacuum. An oily residue with a white solid was recovered. The mixturewas triturated with hexanes and the solid was filtered off to yield aclear oil corresponding to Cap-179, step c (0.34 g). ¹H NMR (500 MHz,CDCl₃) δ ppm 4.21 (1H, quin, J=2.82 Hz), 3.87-3.95 (2H, m), 1.72 (1H,br. s.), 1.63 (2H, dd, J=14.34, 2.14 Hz), 1.39-1.47 (2H, m), 1.17 (6H,d, J=6.41 Hz).

p-Tosyl chloride (3.98 g, 20.89 mmol) was added to a solution ofCap-179, step c (1.36 g, 10.5 mmol) and Pyridine (3.38 mL, 41.8 mmol) inCH₂Cl₂ (150 mL) at room temperature and stirred for 24 h and thenconcentrated to a yellow oil. The remaining residue was added topyridine (20 mL) and water (30 mL) and the resulting mixture was stirredat ambient temperature for 1½ h. The mixture was extracted with Et₂O (75mL) and the separated organic layer was the washed thoroughly with 1 Naq. HCl (4×50 mL). The organic layer was then dried (MgSO₄), filteredand concentrated. A white solid corresponding to Cap-179, step d (2.2 g)was isolated. LC-MS: Anal. Calcd. for [2M+H]⁺ C₂₈H₄₁O₈S₂: 569.22. found569.3. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (2H, d, J=8.28 Hz), 7.35 (2H,d, J=8.03 Hz), 4.89 (1H, quin, J=2.82 Hz), 3.77-3.88 (2H, m), 2.46 (3H,s), 1.77 (2H, dd, J=14.93, 2.89 Hz), 1.36 (2H, ddd, J=14.31, 11.54, 2.76Hz), 1.13 (6H, d, J=6.27 Hz).

LiHMDS (4.30 mL, 4.30 mmol) was added to a solution of Cap-179, step d(1.02 g, 3.59 mmol) and benzyl 2-(diphenylmethyleneamino)acetate (1.181g, 3.59 mmol) in toluene (25 mL) at room temperature in a sealedmicrowave vial and the resulting mixture was then stirred for 5 h at100° C. under microwave radiation. The reaction was quenched with water(10 mL), extracted with EtOAc, washed with water, dried over MgSO₄,filtrated, and concentrated in vacuum. The residue was purified viaBIOTAGE® (0% to 6% EtOAc/Hex; 80 g column) and a yellow oilcorresponding to Cap-179, step e (1.2 g) was isolated. Anal. Calcd. for[2M+Na]⁺ C₅₈H₆₂N₂NaO₆: 905.45. found 905.42. ¹H NMR (400 MHz, CDCl₃) δppm 7.64-7.70 (4H, m), 7.29-7.44 (29H, m), 7.06 (4H, dd, J=7.65, 1.63Hz), 5.18 (2H, d, J=2.01 Hz), 3.89 (2H, d, J=6.53 Hz), 3.79-3.87 (1H,m), 3.46 (5H, dquind, J=11.26, 5.87, 5.87, 5.87, 5.87, 1.88 Hz), 2.47(2H, s), 2.35-2.46 (2H, m), 1.78 (1H, dd, J=14.81, 3.01 Hz), 1.62-1.65(1H, m), 1.61 (2H, s), 1.36-1.43 (3H, m), 1.19 (7H, d, J=6.27 Hz), 1.14(11H, dd, J=6.15, 2.89 Hz), 0.86-0.96 (3H, m).

Cap-179, step e (2.08 g, 4.71 mmol) was dissolved in THF (100 mL) andtreated with 2 N HCl (9.42 mL, 18.84 mmol). The resulting clear solutionwas stirred at ambient temperature for 4 h and then THF was removedunder reduced pressure. The remaining aqueous layer was extracted withhexanes (3×20 ml) and after diluting with H₂O (20 mL), the aqueous phasewas basified with 1 N NaOH to pH=10 and extracted with EtOAc (3×10 mL).The combined organic layers were dried (MgSO₄), filtered andconcentrated under vacuum. The resulting residue was taken up in CH₂Cl₂(100 mL) and charged with DIEA (2.468 mL, 14.13 mmol) and methylchloroformate (0.401 mL, 5.18 mmol). The resulting solution was stirredat ambient temperature for 2 h. The reaction mixture was quenched withwater (10 mL) and the organic layer was removed under reduced pressure.The aqueous layer was then extracted with EtOAc (3×10 mL) and thecombined organic layers were dried (MgSO₄), filtered and concentrated.The residue was purified via BIOTAGE® (10% EtOAc/Hex; 25 g column). Aclear colorless oil corresponding to Cap-179, step f (1.05 g) wasrecovered. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₆NO₅: 336.18. found336.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.32-7.40 (5H, m), 5.26 (1H, d,J=8.24 Hz), 5.13-5.24 (2H, m), 4.36 (1H, dd, J=8.85, 4.88 Hz), 3.68 (3H,s), 3.32-3.46 (2H, m), 2.02-2.14 (1H, m), 1.52 (1H, d, J=12.82 Hz), 1.32(1H, d, J=12.51 Hz), 1.11-1.18 (6H, m), 0.89-1.07 (2H, m).

A chiral SFC method was developed to separate the racemic mixture byusing 12% methanol as the modifier on a CHIRALPAK® AD-H column (30×250mm, 5 μm) (Temp=35° C., Pressure=150 bar, Wavelength=210 nm, Flowrate=70 mL/min for 8 min, Solvent A=CO₂, Solvent B=MeOH). The twoseparated isomers, Cap-179 step f (Enantiomer-1) (first eluting) andCap-179 step f (Enantiomer-2) (second eluting) exhibited the sameanalytical data as the corresponding mixture (see above).

Cap-179 (Enantiomer-1 and Enantiomer-2)

Cap-179 step f (Enantiomer-1) (0.35 g, 1.044 mmol) was dissolved in MeOH(50 mL) in a Parr bottle and charged with Pd/C (0.111 g, 1.044 mmol).The suspension was then placed in a Parr shaker and the mixture wasflushed with N₂ (3×), placed under 40 psi of H₂ (2.104 mg, 1.044 mmol)and shaken at room temperature for 2 h. The catalyst was filtered offthrough a pad of CELITE® and the solvent was removed under reducedpressure, to yield an amber solid corresponding to Cap-179 Enantiomer-1(0.25 g). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.74 (4H, br. s.), 7.35 (4H,d, J=6.10 Hz), 3.85 (4H, br. s.), 3.53 (3H, s), 3.35 (2H, ddd, J=15.95,9.99, 6.10 Hz), 1.97 (1H, br. s.), 1.48 (2H, t, J=13.28 Hz), 1.06 (6H,d, J=6.10 Hz), 0.82-1.00 (2H, m)

Cap-179 Enantiomer-2 was prepared similarly: ¹H NMR (500 MHz, DMSO-d₆) δppm 12.50 (1H, br. s.), 7.31 (1H, br. s.), 3.84 (1H, t, J=7.32 Hz), 3.53(3H, s), 3.29-3.41 (2H, m), 1.99 (1H, s), 1.48 (2H, t, J=14.34 Hz), 1.06(6H, d, J=6.10 Hz), 0.95 (1H, q, J=12.21 Hz), 0.87 (1H, q, J=11.80 Hz).[Note: the minor variation in the ¹H NMR profile of the enantiomers islikely a result of a difference in sample concentration.]

p-Tosyl-Cl (4.39 g, 23.0 mmol) was added to a solution of Cap-179, stepa (1.50 g, 11.5 mmol) and pyridine (3.73 mL, 46.1 mmol) in CH₂Cl₂ (50mL) at room temperature and stirred for 2 days. The reaction was dilutedwith CH₂Cl₂, washed with water, then 1 N HCl. The organic layer wasdried (MgSO₄) and concentrated to a yellow oil which was purified viaBIOTAGE® (5% to 20% EtOAc/Hex; 40 g column). A clear oil that solidifiedunder vacuum and corresponding to Cap-180, step a (2.89 g) was isolated.LC-MS: Anal. Calcd. for [2M+Na]⁺ C₂₈H₄₀NaO₈S₂: 591.21. found 591.3. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.80 (2H, d, J=8.24 Hz), 7.35 (2H, d, J=7.93Hz), 4.59 (1H, tt, J=11.37, 4.96 Hz), 3.36-3.46 (2H, m), 2.46 (3H, s),1.91 (2H, dd, J=12.05, 5.04 Hz), 1.37 (2H, dt, J=12.67, 11.52 Hz), 1.19(6H, d, J=6.10 Hz).

LiHMDS 1 N (7.09 mL, 7.09 mmol) was added to a solution of Cap-180, stepa (1.68 g, 5.91 mmol) and ethyl 2-(diphenylmethyleneamino)acetate (1.579g, 5.91 mmol) in toluene (30 mL) at room temperature and the resultingmixture was then stirred for 16 h at 85° C. The reaction was quenchedwith water (50 mL), extracted with EtOAc, washed with water, dried overMgSO₄, filtrated, and concentrated in vacuo. The residue was purifiedvia BIOTAGE® (0% to 15% EtOAc/Hex; 40 g column). A clear yellowish oilcorresponding to Cap-180, step b (racemic mixture; 0.64 g) was isolated.LC-MS: Anal. Calcd. for [M+H]⁺ C₂₄H₃₀NO₃: 380.22. found 380.03. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.64-7.70 (2H, m), 7.45-7.51 (3H, m), 7.38-7.44(1H, m), 7.31-7.37 (2H, m), 7.13-7.19 (2H, m), 4.39 (1H, d, J=10.54 Hz),4.16-4.26 (2H, m), 3.29-3.39 (1H, m), 2.93-3.03 (1H, m), 2.70 (1H, m,J=9.41, 4.14 Hz), 1.42-1.49 (2H, m), 1.31-1.37 (1H, m), 1.29 (4H, t,J=7.15 Hz), 1.04 (6H, dd, J=7.78, 6.27 Hz).

Cap-180, step b (0.36 g, 0.949 mmol) was dissolved in THF (10 mL) andtreated with 2 N HCl (1.897 mL, 3.79 mmol). The resulting clear solutionwas stirred at ambient temperature for 20 h and THF was removed underreduced pressure. The remaining aqueous layer was extracted with hexanes(3×20 mL) and after diluting with H₂O (20 mL), the aqueous phase wasbasified with 1 N NaOH to pH=10 and extracted with EtOAc (3×10 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentratedunder vacuum. The resulting residue was taken up in CH₂Cl₂ (10.00 mL)and charged with DIEA (0.497 mL, 2.85 mmol) and methyl chloroformate(0.081 mL, 1.044 mmol). The resulting solution was stirred at ambienttemperature for 2 h and the reaction mixture was quenched with water (10mL) and the organic layer was removed under reduced pressure. Aqueouslayer was extracted with EtOAc (3×10 mL) and the combined organic layerswere dried (MgSO₄), filtered and concentrated. An amber oilcorresponding to Cap-180, step c (0.21 g) was recovered and it was usedwithout further purification. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₂₄NO₅:273.17. found 274.06. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.20 (1H, d, J=8.03Hz), 4.59 (1H, t, J=10.16 Hz), 4.11-4.27 (3H, m), 3.69-3.82 (2H, m),3.64 (3H, s), 1.95-2.07 (1H, m), 1.63 (1H, d, J=13.80 Hz), 1.41 (2H, dd,J=8.03, 4.02 Hz), 1.31-1.37 (1H, m), 1.26 (3H, t, J=7.15 Hz), 1.16 (1H,d, J=6.27 Hz), 1.12 (6H, dd, J=6.15, 3.89 Hz).

Cap-180 (Racemic Mixture)

Cap-180, step c (0.32 g, 1.2 mmol) was dissolved in THF (10 mL) andcharged with LiOH (0.056 g, 2.342 mmol) in water (3.33 mL) at 0° C. Theresulting solution was stirred at rt for 2 h. THF was removed underreduced pressure and the remaining residue was diluted with water (15mL) and washed with Et₂O (2×10 mL). The aqueous layer was then acidifiedwith 1N HCl to pH˜2 and extracted with EtOAc (3×15 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated undervacuum to yield Cap-180 (racemic mixture) (0.2 g) as a white foam.LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₀NO₅: 246.13. found 246.00. ¹H NMR(400 MHz, CDCl₃) δ ppm 5.14 (1H, d, J=9.03 Hz), 4.65 (1H, t, J=9.91 Hz),3.63-3.89 (5H, m), 1.99-2.13 (1H, m), 1.56-1.73 (2H, m), 1.48-1.55 (1H,m), 1.35-1.48 (1H, m), 1.27 (1H, br. s.), 1.17 (6H, d, J=6.02 Hz).

A solution of tert-butyl diazoacetate (1.832 mL, 13.22 mmol) in 50 mL ofCH₂Cl₂ was added into a mixture of 2,5-dihydrofuran (9.76 mL, 132 mmol),Rhodium(II) acetate dimer (0.058 g, 0.132 mmol) in 40 mL of CH₂Cl₂dropwise by a syringe pump over 5 hours. The resulting mixture was thenstirred at room temperature overnight. The solvent was removed undervacuum. The residue was purified by chromatography (silica gel, 0%-15%EtOAc/Hex) to afford Cap-181 step a (trans-isomer) (720 mg) and Cap-181,step a (cis-isomer) (360 mg) as clear oil. Cap-181 step a(trans-isomer): ¹H NMR (500 MHz, CDCl₃) δ ppm 3.88 (2H, d, J=8.55 Hz),3.70 (2H, d, J=8.55 Hz), 2.03-2.07 (2H, m), 1.47 (1H, t, J=3.20 Hz),1.41 (9H, s); Cap-1, step a (cis-isomer): ¹H NMR (400 MHz, CDCl₃) δ ppm4.06 (2H, d, J=8.53 Hz), 3.73 (2H, d, J=8.03 Hz), 1.81-1.86 (2H, m),1.65-1.71 (1H, m), 1.43-1.47 (9H, m).

To a solution of (Cap-181, step a (trans-isomer)) (700 mg, 3.80 mmol) in15 mL of diethyl ether at −10° C. was added LiAlH4 (7.60 mL, 7.60 mmol)(1 M in THF) dropwise over 1 hour. The resulting mixture was stirred at−10° C. for 1 hour then at room temperature for 1 hour. The mixture wasthen cooled to −5° C. 10 mL of Rochelle's salt (potassium sodiumtartrate) aqueous solution was added dropwise to quench the reaction.The mixture was stirred at room temperature for 30 min and thenextracted with EtOAc (3×). The combined organic layers were dried withMgSO₄ and concentrated to afford Cap-181, step b (380 mg) as lightyellow oil. The product was used in the next step without purification.¹H NMR (400 MHz, CDCl₃) δ ppm 3.85 (2H, d, J=8.28 Hz), 3.68 (2H, d,J=8.53 Hz), 3.45-3.55 (2H, m), 1.50-1.56 (2H, m), 1.02-1.11 (1H, m).

To a solution of DMSO (4.82 mL, 67.9 mmol) in CH₂Cl₂ (70 mL) was addeddropwise oxalyl chloride (3.14 mL, 35.8 mmol) at −78° C. The resultingmixture was stirred at −78° C. for 15 min. A solution of Cap-181, step b(3.10 g, 27.2 mmol) in 35 mL of CH₂Cl₂ was added and the mixture wasstirred at −78° C. for 1 hour. Et₃N (18.93 mL, 136 mmol) was then addeddropwise. After 30 min, the cooling bath was removed and the reactionwas quenched with cold 20% K₂HPO₄ aq. solution (10 mL) and water. Themixture was stirred at room temperature for 15 min and then diluted withEt₂O. The layers were separated. The aqueous layer was extracted withEt₂O (2×). The combined organic layers were washed with brine, driedwith MgSO₄ and concentrated. The residue was purified by flashchromatography (silica gel, 100% CH₂Cl₂) to afford Cap-181, step c (2.71g) as light yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.41 (1H, d,J=4.27 Hz), 3.96 (2H, d, J=8.85 Hz), 3.80 (2H, d, J=8.55 Hz), 2.27-2.33(2H, m), 1.93 (1H, m).

To a mixture of Cap-181, step c (2.7 g, 24.08 mmol) in 50 mL of water at0° C. was added sodium bisulfite (2.506 g, 24.08 mmol) and KCN (1.631 g,25.04 mmol), followed by a solution of (R)-2-amino-2-phenylethanol (3.30g, 24.08 mmol) in 18 mL of MeOH. The resulting mixture was stirred atroom temperature for 2 hours and then heated to reflux overnight. Themixture was cooled to room temperature. 100 mL of EtOAc was added. Aftermixing for 15 min, the layers were separated. The aqueous layer wasextracted with EtOAc (2×). The combined organic layers were washed withbrine, dried with MgSO₄ and concentrated. The crude diastereomericmixture was purified by reverse phase HPLC (Column: Water Sunfire 30×150mm, acetonitrile/water/NH₄OAc) to afford a two diastereomers of Cap-181,step d. The absolute stereochemistry of each isomer was not determined.Diastereomer 1 (later eluting fraction) (570 mg): LC-MS: Anal. Calcd.for [M+H]⁺ C₁₈H₁₉N₂O₂ 259.14. found 259.2.

To a solution of Cap-181, step d (diastereomer 1) (570 mg, 2.207 mmol)in 20 mL of CH₂Cl₂ and 20 mL of MeOH at 0° C. was added leadtetraacetate (1174 mg, 2.65 mmol). The resulting orange mixture wasstirred at 0° C. for 10 min. Water (20 mL) was then added into themixture and the mixture was filtered off (CELITE®). The filtrate wasconcentrated and diluted with 25 mL of 6 N HCl aq. solution. Theresulting mixture was refluxed for 4 hours. The mixture was filtered offand washed with CH₂Cl₂. The aqueous layer was concentrated to affordCap-181, step e (HCl salt). The crude product was used in the next stepwithout further purification. ¹H NMR (500 MHz, MeOD) δ ppm 3.87-3.91(2H, m), 3.73 (2H, dd, J=8.70, 2.90 Hz), 3.55 (1H, d, J=10.07 Hz),2.02-2.07 (1H, m), 1.94-1.99 (1H, m), 1.03-1.10 (1H, m).

Cap-181

To a mixture of the above crude Cap-181, step e in 1 N NaOH aq. solution(10 mL) was added sodium bicarbonate (371 mg, 4.42 mmol). Methylchloroformate (0.342 mL, 4.42 mmol) was then added dropwise, and theresulting mixture was stirred at room temperature for 3 hours. Themixture was neutralized with 1 N HCl aq. Solution and extracted withEtOAc (3×). The combined organic layers were dried with MgSO₄ andconcentrated to afford Cap-181 (100 mg, 21% over two steps) as lightyellow oil. LC-MS: Anal. Calcd. for [M+H]⁺ C₉H₁₄NO₅ 216.09. found 216.1.¹H NMR (500 MHz, CDCl₃) δ ppm 5.29 (1H, br. s.), 3.53-4.02 (8H, m),1.66-1.92 (2H, m), 1.08 (1H, br. s.).

A solution of cyclopent-3-enol (5 g, 59.4 mmol) and Et₃N (9.94 mL, 71.3mmol) in 50 mL of CH₂Cl₂ was stirred at room temperature for 15 min.Benzoyl chloride (8.28 mL, 71.3 mmol) was then added dropwise and themixture was stirred at room temperature overnight. The mixture was thenwashed with water, and the organic layer was dried with MgSO₄ andconcentrated. The residue was purified by flash chromatography (silicagel, EtOAc/Hex 0-10%) to afford Cap-182, step a (9.25 g) as clear oil.¹H NMR (400 MHz, CDCl₃) δ ppm 8.01-8.07 (2H, m), 7.55 (1H, t, J=7.40Hz), 7.43 (2H, t, J=7.65 Hz), 5.79 (2H, s), 5.64 (1H, tt, J=6.93, 2.60Hz), 2.87 (2H, dd, J=16.56, 6.78 Hz), 2.52-2.63 (2H, m).

To a round bottom flask with a magnetic stirring bar was added sodiumfluoride (5.02 mg, 0.120 mmol) and Cap-182, step a (2.25 g, 11.95 mmol).The flask was heated up to 100° C. and neat trimethylsilyl2,2-difluoro-2-(fluorosulfonyl)acetate (5.89 mL, 29.9 mmol) was addedslowly by syringe pump over 5 hours, and heated at 100° C. overnight.The mixture was then diluted with CH₂Cl₂, washed with water, sat. NaHCO₃aq. solution and brine, dried with MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography (silica gel, 0-5%EtOAc/Hex) to afford Cap-182, step b (isomer 1) (750 mg) and Cap-182,step b (isomer 2) (480 mg) as clear oils. Relative stereochemicalassignment was made by NOE study. Cap-182, step b (isomer 1): LC-MS:Anal. Calcd. for [M+H]⁺ C₁₃H₁₃F₂O₂ 239.09. found 239.2. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.99-8.04 (2H, m), 7.56 (1H, t, J=7.32 Hz), 7.43 (2H, t,J=7.63 Hz), 5.25-5.33 (1H, m), 2.50 (2H, dd, J=14.04, 6.71 Hz),2.14-2.22 (2H, m), 2.08-2.14 (2H, m). Cap-182, step b (isomer 2): LC-MS:Anal. Calcd. for [M+H]⁺ C₁₃H₁₃F₂O₂ 239.09. found 239.2. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.98-8.08 (2H, m), 7.53-7.59 (1H, m), 7.41-7.48 (2H, m),5.53-5.62 (1H, m), 2.59-2.70 (2H, m), 2.01-2.11 (4H, m).

To a solution of Cap-182, step b (isomer 2) (480 mg, 2.015 mmol) in 4 mLof MeOH was added KOH (4 mL, 2.015 mmol) (10% aq.). The resultingmixture was stirred at room temperature overnight. The mixture was thenextracted with CH₂Cl₂ (3×). The combined organic layers were dried withMgSO₄ and concentrated to afford Cap-182, step c (220 mg) as a lightyellow solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.41-4.54 (1H, m), 2.38-2.50(2H, m), 1.89-1.99 (2H, m), 1.81 (2H, dd, J=14.50, 5.04 Hz).

p-Tosyl-Cl (625 mg, 3.28 mmol) was added to a solution of Cap-182, stepc (220 mg, 1.640 mmol) and pyridine (0.531 mL, 6.56 mmol) in 7 mL ofCH₂Cl₂. The mixture was stirred at room temperature overnight and thendiluted with CH₂Cl₂, washed with water and 1 N HCl aq. solution. Theorganic layer was dried (MgSO₄) and concentrated. The residue waspurified by flash chromatography (silica gel, 0-15% EtOAc/Hexane) toafford Cap-182, step d (325 mg) as a clear oil. LC-MS: Anal. Calcd. For[M+Na]⁺ C₁₃H₁₄F₂NaO₃S 311.05. found 311.2. ¹H NMR (500 MHz, CDCl₃) δ ppm7.76 (2H, d, J=8.24 Hz), 7.34 (2H, d, J=8.24 Hz), 4.99-5.08 (1H, m),2.45 (3H, s), 2.31-2.41 (2H, m), 1.84-1.94 (4H, m).

To a microwave tube was added N-(diphenylmethylene)glycine ethyl ester(241 mg, 0.902 mmol) and Cap-182, step d (260 mg, 0.902 mmol) in 2 mL oftoluene. The tube was sealed and LiHMDS (1.082 mL of 1 N in THF, 1.082mmol) was added dropwise under N₂. The resulting dark brown solution washeated at 100° C. in microwave for 5 hours. The mixture was thenquenched with water, and extracted with EtOAc (3×). The combined organiclayers were washed with water, dried with MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (silica gel, 0-5%EtOAc/Hex) to afford a racemic mixture of Cap-182, step e (240 mg) aslight yellow oil. The mixture was submitted to the next step withoutseparation. LC-MS: Anal. Calcd. for [M+H]⁺ C₂₃H₂₄F₂NO₂ 384.18. found384.35. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.63-7.70 (2H, m), 7.43-7.51 (3H,m), 7.38-7.43 (1H, m), 7.31-7.38 (2H, m), 7.13-7.22 (2H, m), 4.13-4.22(2H, m), 3.95 (1H, d, J=6.41 Hz), 2.67-2.79 (1H, m), 2.07-2.16 (1H, m),1.97-2.07 (2H, m), 1.90 (2H, m), 1.65-1.76 (1H, m), 1.25 (3H, t, J=7.17Hz).

To a solution of Cap-182, step e (240 mg, 0.626 mmol) in 4 mL of THF wasadded HCl (1 mL, 2.0 mmol) (2 N aq.). The resulting mixture was stirredat room temperature for 2 hours. The mixture was then washed with EtOAc,neutralized with sat. NaHCO₃ aq. solution and then extracted with EtOAc(3×). The combined organic layers were dried with MgSO₄ and concentratedto afford Cap-182, step f (120 mg) as clear oil. LC-MS: Anal. Calcd. for[M+H]⁺ C₁₀H₁₆F₂NO₂ 220.11. found 220.26. ¹H NMR (500 MHz, CDCl₃) δ ppm4.14-4.25 (2H, m), 3.26 (1H, d, J=6.71 Hz), 2.22-2.35 (1H, m), 1.90-2.11(5H, m), 1.79-1.90 (1H, m), 1.22-1.34 (3H, m).

To a solution of Cap-182, step f (120 mg, 0.547 mmol) in 2 mL of CH₂Cl₂was added methyl chloroformate (0.085 mL, 1.095 mmol). The resultingmixture was stirred at room temperature for 1 hour. The mixture wasdiluted with CH₂Cl₂ and washed with water. The organic layer was driedwith Na₂SO₄ and concentrated to afford Cap-182, step g (150 mg) as awhite solid. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₈F₂NO₄ 278.12. found278.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.23 (1H, d, J=8.24 Hz), 4.29 (1H,t, J=7.48 Hz), 4.15-4.23 (2H, m), 3.68 (3H, s), 2.37 (1H, br. s.),2.02-2.10 (1H, m), 1.85-2.00 (4H, m), 1.75-1.84 (1H, m), 1.27 (3H, t,J=7.02 Hz).

Cap-182 (Racemic Mixture)

To a mixture of Cap-182, step g (150 mg, 0.541 mmol) in 2 mL of THF and1 mL of water was added LiOH (0.811 mL, 1.623 mmol) (2 N aq.). Theresulting mixture was stirred at room temperature overnight. The mixturewas neutralized with 1 N HCl aq. solution and extracted with EtOAc (3×).The combined organic layers were dried with MgSO₄ and concentrated toafford Cap-182 (133 mg) as a white solid. LC-MS: Anal. Calcd. for [M+H]⁺C₁₀H₁₄F₂NO₄ 250.09. found 250.13. ¹H NMR (500 MHz, CDCl₃) δ ppm5.18-5.36 (1H, m), 4.28-4.44 (1H, m), 3.70 (3H, s), 2.37-2.56 (1H, m),1.74-2.31 (6H, m).

Cap-183 was synthesized from Cap-182, step b (isomer 1) according to theprocedure described for the preparation of Cap-182. Anal. Calcd. for[M+H]⁺ C₁₀H₁₄F₂NO₄ 250.09. found 249.86. ¹H NMR (500 MHz, CDCl₃) δ ppm5.15 (1H, d, J=8.24 Hz), 4.32 (1H, t, J=7.48 Hz), 3.69 (3H, s),2.83-2.99 (1H, m), 1.96-2.26 (4H, m), 1.70 (1H, t, J=11.75 Hz), 1.59(1H, t, J=12.05 Hz).

A mixture of ethyl2-amino-2-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)acetate (prepared fromcommercially available (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol by employingthe same procedures described for the preparation of Cap-182; 350 mg,1.910 mmol), DiPEA (0.667 mL, 3.82 mmol), methyl chloroformate (0.296mL, 3.82 mmol) in 5 mL of CH₂Cl₂ was stirred at room temperature for 1hour. The mixture was then diluted with CH₂Cl₂ and washed with water.The organic layer was dried with MgSO₄ and concentrated to affordCap-184 step a (461 mg) as yellow oil. LC-MS: Anal. Calcd. for [M+H]⁺C₁₂H₂₀NO₄ 242.14. found 242.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.04 (1H,d, J=7.63 Hz), 4.09-4.20 (2H, m), 4.05 (1H, t, J=8.39 Hz), 3.63 (3H, s),2.55-2.70 (1H, m), 1.96-2.09 (2H, m), 1.37-1.60 (4H, m), 1.24 (3H, t,J=7.17 Hz), 0.66-0.76 (1H, m), −0.03-0.06 (1H, m).

Cap-184 (Racemic Mixture)

To a mixture of ethyl ester Cap-184, step a (461 mg, 1.911 mmol) in 5 mLof THF and 2 mL of water was added LiOH (2.87 mL, 5.73 mmol) (2 N aq.).The resulting mixture was stirred at room temperature overnight. Themixture was then neutralized with 1 N HCl aqueous solution, andextracted with EtOAc (3×). The combined organic layers were dried withMgSO₄ and concentrated to afford Cap-184 (350 mg) as clear oil. LC-MS:Anal. Calcd. for [2M+Na]⁺ C₂₀H₃₀N₂NaO₈ 449.19. found 449.3. ¹H NMR (500MHz, CDCl₃) δ ppm 5.07 (1H, d, J=8.85 Hz), 4.13 (1H, t, J=8.24 Hz), 3.68(3H, s), 2.64-2.79 (1H, m), 2.04-2.21 (2H, m), 1.23-1.49 (4H, m),0.71-0.81 (1H, m), 0.03-0.12 (1H, m).

To a mixture of furan (1.075 mL, 14.69 mmol) and zinc (1.585 g, 24.24mmol) in 1 ml, of THF was added 1,1,3,3-tetrabromopropan-2-one (8.23 g,22.03 mmol) and triethyl borate (5.25 mL, 30.8 mmol) in 4 mL of THFdropwise during 1 hour in dark. The resulting mixture was stirred atroom temperature in dark for 17 hours. The resulting dark brown mixturewas cooled to −15° C., and 6 mL of water was added. The mixture waswarmed to 0° C. and stirred at this temperature for 30 min. The mixturewas then filtered and washed with ether. The filtrate was diluted withwater and extracted with ether (3×). The combined organic layers weredried with MgSO₄ and concentrated to afford dark brown oil. The darkbrown oil was dissolved in 6 mL of MeOH and the solution was addeddropwise to a mixture of zinc (4.99 g, 76 mmol), copper (I) chloride(0.756 g, 7.64 mmol) and ammonium chloride (5.4 g, 101 mmol) in 20 mL ofMeOH. The reaction temperature was maintained below 15° C. duringaddition. The mixture was then stirred at room temperature for 20 hours,filtered, and the filtrate was diluted with water and extracted withCH₂Cl₂ (3×). The combined organic layers were dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 0-14% EtOAc/Hex) to afford Cap-185, step a as a white solid(1.0 g) as a white solid, which turned yellow soon. ¹H NMR (500 MHz,CDCl₃) δ ppm 6.24 (2H, s), 5.01 (2H, d, J=4.88 Hz), 2.73 (2H, dd,J=16.94, 5.04 Hz), 2.31 (2H, d, J=16.79 Hz).

To a solution of Cap-185, step a (240 mg, 1.933 mmol) in 2 mL of THF at−78° C. was added L-selectride (3.87 mL, 3.87 mmol) (1 M in THF)dropwise over 100 min. The resulting mixture was stirred at −78° C. for1 hour and then at room temperature overnight. The mixture was thencooled to 0° C., 4 mL of 20% NaOH aqueous solution was added, followedby 2 mL of H₂O₂ (30% water solution) dropwise. The resulting mixture wasstirred for 1 hour and then neutralized with 6N HCl (˜5 mL). The aqueouslayer was saturated with NaCl and extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried with MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (silica gel, 0-40%EtOAc/Hex) to afford Cap-185, step b (180 mg) as clear oil. ¹H NMR (400MHz, CDCl₃) δ ppm 6.49 (2H, s), 4.76 (2H, d, J=4.27 Hz), 3.99 (1H, t,J=5.77 Hz), 2.29 (2H, ddd, J=15.18, 5.65, 4.02 Hz), 1.70-1.78 (2H, m).

p-Tosyl-Cl (544 mg, 2.85 mmol) was added to a solution of Cap-185, stepb (180 mg, 1.427 mmol) and pyridine (0.462 mL, 5.71 mmol) in 5 mL ofCH₂Cl₂ (5 mL) and the mixture was stirred at room temperature for 2days. The reaction was diluted with CH₂Cl₂ and washed with 1 N aq. HCl.The aqueous layer was extracted with CH₂Cl₂ (2×). The combined organiclayers were dried with MgSO₄ and concentrated. The crude product waspurified by flash chromatography (silica gel, 0-15% EtOAc/Hex) to affordCap-185, step c (210 mg) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm7.73 (2H, d, J=8.24 Hz), 7.32 (2H, d, J=8.24 Hz), 6.25 (2H, s), 4.76(1H, t, J=5.65 Hz), 4.64 (2H, d, J=3.66 Hz), 2.44 (3H, s), 2.18 (2H, td,J=10.07, 5.49 Hz), 1.71 (2H, d, J=15.56 Hz).

A microwave tube was charged with benzyl2-(diphenylmethyleneamino)acetate (1.5 g, 4.57 mmol) and Cap-185, step c(1.28 g, 4.57 mmol) in 5 mL of toluene. The tube was sealed and LiHMDS(5.5 mL, 5.5 mmol) (1 N in toluene) was added dropwise under N₂. Theresulting dark brown solution was heated at 100° C. in microwave for 5hours. To the mixture was then added water and EtOAc. The layers wereseparated and the water phase was extracted with EtOAc (2×). Thecombined organic layers were concentrated to afford Cap-185, step d as aracemic mixture of. The crude mixture was submitted to the next stepwithout purification or separation. LC-MS: Anal. Calcd. for [M+H]⁺C₂₉H₂₈NO₃ 438.21. found 438.4.

To a solution of the racemic mixture of Cap-185, step d in 30 mL of THFwas added HCl (20 mL) (2 N aq.). The resulting mixture was stirred atroom temperature for 2 hours. After the reaction was done as judged byTLC, the two layers were separated. The aqueous layer was washed withEtOAc, neutralized with sat. NaHCO₃ aq. solution and then extracted withEtOAc (3×). The combined organic layers were dried with MgSO₄ andconcentrated to afford Cap-185, step e. LC-MS: Anal. Calcd. for [M+H]⁺C₁₆H₂₀NO₃ 274.14. found 274.12.

A solution of the crude Cap-185, step e, DiPEA (1.24 mL, 7.1 mmol) andmethyl chloroformate (0.55 mL, 7.1 mmol) in 5 mL of CH₂Cl₂ was stirredat room temperature for 1 hour. The mixture was then diluted with CH₂Cl₂and washed with water. The organic layer was dried with Na₂SO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 0-40% EtOAc/Hex) to afford 700 mg of the racemic mixture.The mixture was then separated by chiral HPLC (CHIRALPAK® AD-H column,30×250 mm, 5 um) eluting with 88% CO₂-12% EtOH at 70 mL/min to afford240 mg of Enantiomer-1 and 310 mg of Enantiomer-2 of Cap-1, step f aswhite solids. Enantiomer-1: LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₂NO₅332.15. found 332.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.30-7.40 (5H, m),6.03-6.16 (2H, m), 5.09-5.26 (3H, m), 4.65-4.74 (2H, m), 4.33 (1H, dd,J=9.16, 4.88 Hz), 3.67 (3H, s), 2.27-2.38 (1H, m), 1.61-1.69 (1H, m),1.45-1.56 (1H, m), 1.34 (1H, dd, J=13.43, 5.19 Hz), 1.07 (1H, dd,J=13.12, 5.19 Hz). Enantiomer-2: LC-MS: Anal. Calcd. for [M+H]⁺C₁₈H₂₂NO₅ 332.15. found 332.06.

Cap-185 (Enantiomer-1 and Enantiomer-2)

To a hydrogenation bottle containing a solution Cap-185, step f(Enantiomer-2) (300 mg, 0.905 mmol) in 10 mL of MeOH was added Pd/C (15mg, 0.141 mmol) under a cover of nitrogen. The mixture was hydrogenatedon a Parr shaker at 40 psi for 3 hours. The mixture was then filteredand the filtrate was concentrated to afford Cap-185 (Enantiomer-2) (200mg) as a white solid. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₈NO₅ 244.12.found 244.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.33 (1H, br. s.), 4.46 (2H,d), 4.28 (1H, br. s.), 3.68 (3H, s), 2.35 (1H, br. s.), 1.91-2.03 (2H,m), 1.56-1.80 (4H, m), 1.36-1.55 (2H, m). [Note: Cap-185 (Enantiomer-1)can be obtained in a similar fashion.]

To a solution of the ester Cap-185, step f (Enantiomer-2) (150 mg, 0.453mmol) in 4 mL of MeOH was added NaOH (4 mL of 1 N in water, 4.00 mmol).The resulting mixture was stirred at room temperature for 3 hours. Themethanol was then removed under vacuum, and the residue was neutralizedwith 1 N HCl solution and extracted with EtOAc (3×). The combinedorganic layers were dried with MgSO₄ and concentrated to afford Cap-186that was contaminated with some benzyl alcohol (sticky white solid; 115mg). LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₅ 242.10. found 242.1. ¹HNMR (500 MHz, CDCl₃) δ ppm 6.10-6.19 (2H, m), 5.36 (1H, d, J=8.85 Hz),4.75-4.84 (2H, m), 4.28 (1H, dd, J=8.55, 4.58 Hz), 3.68 (3H, s),2.33-2.45 (1H, m), 1.60-1.72 (2H, m), 1.30-1.48 (2H, m).

To a solution of Cap-178, step e (2.2 g, 18.94 mmol), PPh₃ (24.84 g, 95mmol) and 4-nitrobenzoic acid (14.24 g, 85 mmol) in 30 mL of benzene wasadded DEAD (42.9 mL, 95 mmol) dropwise. The resulting light orangesolution was stirred at room temperature overnight. The solvent was thenremoved under vacuum and the residue was purified by flashchromatography (silica gel, 0-15% EtOAc/Hex) to afford Cap-187, step a(2.3 g) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.27-8.34 (2H,m), 8.20-8.26 (2H, m), 5.45 (1H, t, J=2.90 Hz), 3.83-3.96 (3H, m),1.90-2.03 (2H, m), 1.80-1.88 (1H, m), 1.61-1.70 (1H, m), 1.21 (3H, d,J=6.10 Hz).

To a solution of Cap-187, step a (2.3 g, 8.67 mmol) in 10 mL of MeOH wasadded sodium methoxide (2.372 mL, 8.67 mmol) (25% in Methanol). Theresulting mixture was stirred at room temperature for 3 hours. Water wasadded, and the mixture was extracted with EtOAc (5×). The combinedorganic layers were dried with MgSO₄ and concentrated. The crude productwas purified by flash chromatography (silica gel, 0-15% EtOAc/Hex, then15-50% EtOAc/Hex) to afford Cap-187, step b (0.85 g) as clear oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 4.19-4.23 (1H, m), 3.82-3.91 (2H, m),3.73-3.79 (1H, m), 1.79-1.88 (1H, m), 1.62-1.68 (1H, m), 1.46-1.58 (2H,m), 1.14 (3H, d, J=6.10 Hz).

Cap-187

The individual enantiomers of Cap-187 were synthesized from Cap-187,step b according to the procedure described for Cap-178. LC-MS: Anal.Calcd. for [M+H]⁺ C₁₀H₁₈NO₅ 232.12. found 232.1. ¹H NMR (400 MHz, CDCl₃)δ ppm 5.26 (1H, d, J=7.78 Hz), 4.32-4.43 (1H, m), 4.07 (1H, dd, J=11.54,3.51 Hz), 3.72 (3H, s), 3.39-3.50 (2H, m), 2.08-2.23 (1H, m), 1.54-1.68(1H, m), 1.38-1.52 (1H, m), 1.11-1.32 (5H, m).

To a solution of 2,2-dimethyldihydro-2H-pyran-4(3H)-one (2 g, 15.60mmol) in 50 mL of MeOH was slowly added sodium borohydride (0.649 g,17.16 mmol). The resulting mixture was stirred at room temperature for 3hours. To the mixture was then added 1 N HCl aqueous solution until itcrosses into acidic pH range and then extracted with EtOAc (3×). Thecombined organic layers were dried with MgSO₄ and concentrated to affordCap-188, step a (1.9 g) as clear oil. The product was used in the nextstep without purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.91-4.02 (1H,m), 3.79-3.86 (1H, m), 3.63 (1H, td, J=12.05, 2.51 Hz), 1.82-1.93 (2H,m), 1.40-1.53 (1H, m), 1.29-1.38 (1H, m), 1.27 (3H, s), 1.20 (3H, s).

p-Tosyl-Cl (5.56 g, 29.2 mmol) was added to a solution of Cap-188, stepa (1.9 g, 14.59 mmol) and pyridine (4.72 mL, 58.4 mmol) in 100 mL ofCH₂Cl₂. The resulting mixture was stirred at room temperature for 3days. To the reaction was added 10 mL of water, and the mixture wasstirred at room temperature for an additional hour. The two layers wereseparated and the organic phase was washed with water and 1 N HClaqueous solution. The organic phase was dried with MgSO₄ andconcentrated to afford the mixture of two enantiomers as a light yellowsolid. The mixture was then separated by chiral HPLC (CHIRALPAK® ADcolumn, 21×250 mm, 10 um) eluting with 92% 0.1% diethylamine/Heptane-8%EtOH at 15 mL/min to afford Cap-188.1, step b (1.0 g) and Cap-188.2,step b (1.0 g). The absolute stereochemistry of the two enantiomers wasnot assigned. Cap-188.1, step b: LC-MS: Anal. Calcd. for [2M+Na]⁺C₂₈H₄₀NaO₈S₂ 591.21. found 591.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.79(2H, d, J=8.24 Hz), 7.34 (2H, d, J=8.24 Hz), 4.72-4.81 (1H, m), 3.78(1H, dt, J=12.44, 4.16 Hz), 3.53-3.61 (1H, m), 2.45 (3H, s), 1.75-1.86(2H, m), 1.61-1.71 (1H, m), 1.52-1.60 (1H, m), 1.22 (3H, s), 1.14 (3H,s). Cap-188.2, step b: LC-MS: Anal. Calcd. for [2M+Na]⁺ C₂₈H₄₀NaO₈S₂591.21. found 591.3.

Cap-188

The four stereoisomers of Cap-188 could be synthesized from Cap-188.1,step b and Cap-188.2, step b, according to the procedure described forthe preparation of Cap-178. Cap-188 (Steroisomer-1): LC-MS: Anal. Calcd.for [M+Na]⁺ C₁₁H₁₉NNaO₅ 268.12. found 268.23. ¹H NMR (500 MHz, CDCl₃) δppm 5.32 (1H, d, J=8.55 Hz), 4.26-4.35 (1H, m), 3.57-3.82 (5H, m),2.11-2.34 (1H, m), 1.25-1.58 (4H, m), 1.21 (6H, d, J=6.10 Hz). Cap-188(Stereoisomer-2): LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₀NO₅ 246.13. found246.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.25 (1H, d, J=8.55 Hz), 4.33 (1H,dd, J=8.39, 5.04 Hz), 3.80 (1H, dd, J=11.90, 3.97 Hz), 3.62-3.76 (4H,m), 2.20-2.32 (1H, m), 1.52-1.63 (1H, m), 1.27-1.49 (3H, m), 1.22 (6H,d, J=14.04 Hz).

To a solution of phenylmagnesium bromide (113 mL, 340 mmol) (3 M inether) in 100 mL of ether was added dropwise exo-2,3-epoxynorbornane (25g, 227 mmol) in 50 mL of ether. After the initial exotherm, the mixturewas heated to reflux overnight. The reaction was then cooled to roomtemperature and quenched carefully with water (˜10 mL). The mixture wasdiluted with ether and washed with a 3 N HCl aqueous solution (˜160 mL).The aqueous layer was extracted with ether (2×) and the combined organiclayers were dried with MgSO₄ and concentrated. The crude product waspurified by flash chromatography (silica gel, 0-18% EtOAc/Hex) to affordCap-189, step a (11 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.03-6.11 (2H, m),3.76 (1H, d, J=11.29 Hz), 2.72-2.81 (2H, m), 1.98 (1H, d, J=11.29 Hz),1.67-1.76 (2H, m), 0.90-0.97 (2H, m).

To a solution of oxalyl chloride (59.9 mL, 120 mmol) in 200 mL of CH₂Cl₂at −78° C. was added DMSO (17.01 mL, 240 mmol) in 100 mL of CH₂Cl₂. Themixture was stirred for 10 min, and Cap-189, step a (11 g, 100 mmol) in150 mL of CH₂Cl₂ was added followed by Et₃N (72.4 mL, 519 mmol) in 30 mLof CH₂Cl₂. The mixture was stirred at −78° C. for 30 min and then warmedto room temperature. Water (150 mL) was added and the mixture wasstirred at room temperature for 30 mins. The two layers were thenseparated, and the aqueous layer was extracted with CH₂Cl₂ (2×). Theorganic layers were combined, dried with MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (silica gel, 0-5%EtOAc/Hex) to afford Cap-189, step b (5.3 g) as a light yellow oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 6.50-6.55 (2H, m), 2.78-2.84 (2H, m),1.92-1.99 (2H, m), 1.17-1.23 (2H, m).

A mixture of Cap-189, step b (5.3 g, 49.0 mmol), p-toluenesulfonic acidmonohydrate (1.492 g, 7.84 mmol) and ethylene glycol (4.10 mL, 73.5mmol) in 100 mL of benzene was refluxed for 4 hours and then stirred atroom temperature overnight. The reaction was partitioned between Et₂Oand aqueous sat. NaHCO₃ solution and the two layers were separated. Theorganic layer was washed with brine, dried with MgSO₄ and concentrated.The crude product was purified by flash chromatography (silica gel, 0-6%EtOAc/Hex) to afford Cap-189, step c (5.2 g) as a clear oil. ¹H NMR (400MHz, CDCl₃) δ ppm 6.20 (2H, t, J=2.13 Hz), 3.90-3.97 (2H, m), 3.81-3.89(2H, m), 2.54 (2H, m), 1.89-1.99 (2H, m), 0.95-1.03 (2H, m).

A solution of Cap-189, step c (5.2 g, 34.2 mmol) in 60 mL of MeOH and 50mL of CH₂Cl₂ was cooled to −78° C. and treated with ozone gas until alight blue color was apparent. The reaction was then bubbled with N₂ toremove the excess ozone gas (blue color disappeared) and sodiumborohydride (1.939 g, 51.3 mmol) was added into the reaction. Thereaction was then warmed to 0° C. Acetone was added into the mixture toquench the excess sodium borohydride. The mixture was concentrated andthe residue was purified by flash chromatography (silica gel, 100%EtOAc) to afford Cap-189, step d (5.0 g) as a clear oil. ¹H NMR (400MHz, CDCl₃) δ ppm 3.99-4.09 (4H, m), 3.68 (4H, m), 2.17-2.29 (2H, m),1.92-2.10 (2H, m), 1.77-1.88 (2H, m), 1.57-1.70 (2H, m).

To a solution of Cap-189, step d (1 g, 5.31 mmol) in 20 mL of CH₂Cl₂ wasadded silver oxide (3.8 g), p-Ts-Cl (1.215 g, 6.38 mmol) and KI (0.176g, 1.063 mmol). The resulting solution was stirred at room temperaturefor 3 days. The mixture was then filtered and the filtrate wasconcentrated. The crude product was purified by flash chromatography(silica gel, 60% EtOAc/Hex) to afford Cap-189, step e (0.79 g) as clearoil. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₆H₂₂NaO₆S 365.10. found 365.22.¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (2H, d, J=8.28 Hz), 7.36 (2H, d,J=8.03 Hz), 4.11-4.17 (1H, m), 3.85-4.06 (5H, m), 3.64-3.71 (1H, m),3.55-3.63 (1H, m), 2.47 (3H, s), 2.32-2.43 (1H, m), 2.15-2.27 (1H, m),1.70-1.89 (2H, m), 1.52-1.66 (1H, m), 1.35-1.47 (1H, m).

To a solution of Cap-189, step e (2.2 g, 6.43 mmol) in 40 mL of MeOH wasadded potassium carbonate (1.776 g, 12.85 mmol). The resulting mixturewas stirred at room temperature overnight. The mixture was then dilutedwith water and EtOAc. The two layers were separated. The aqueous layerwas extracted with EtOAc (2×). The combined organic layers were washedwith brine, dried with MgSO₄ and concentrated. The crude product waspurified by flash chromatography (silica gel, 0-15% EtOAc/Hex) to affordCap-189, step f (0.89 g, 5.23 mmol, 81%) as clear oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 3.89-4.02 (6H, m), 3.58 (2H, dd, J=10.79, 2.51 Hz),1.69-1.89 (6H, m).

To the solution of Cap-189, step f (890 mg, 5.23 mmol) in 15 mL of THFwas added HCl (15 mL, 45.0 mmol) (3 M aqueous). The resulting mixturewas stirred at room temperature overnight. The mixture was then dilutedwith ether and the two layers were separated. The aqueous phase wasextracted with ether (2×) and the combined organic layers were driedwith MgSO₄ and concentrated to afford Cap-189, step g (0.95 g,containing some residual solvents). The product was used in the nextstep without purification. ¹H NMR (500 MHz, CDCl₃) δ ppm 3.95-4.00 (2H,m), 3.85 (2H, d, J=10.68 Hz), 2.21-2.28 (2H, m), 1.99-2.04 (2H, m),1.90-1.96 (2H, m).

To a solution of (+/−)-benzyloxycarbonyl-α-phosphonoglycine trimethylester (1733 mg, 5.23 mmol) in 6 mL of THF at −20° C. was added1,1,3,3-tetramethylguanidine (0.723 mL, 5.75 mmol). The resultant lightyellow mixture was stirred at −20° C. for 1 hour, and Cap-189, step g(660 mg, 5.23 mmol) in 3 mL of THF was added and mixture was thenstirred at room temperature for 3 days. The reaction mixture was thendiluted with EtOAc, washed with a 0.1 N HCl aq. solution. The aqueouslayer was extracted with EtOAc (2×) and the combined organic layers weredried with MgSO₄ and concentrated. The crude product was purified byflash chromatography (silica gel, 0-4% EtOAc/CH₂Cl₂) to afford 960 mg ofthe racemic mixture. The mixture was separated by chiral HPLC(CHIRALPAK® AD column, 21×250 mm, 10 um) eluting with 90% 0.1%diethylamine/Heptane-10% EtOH at 15 mL/min to afford Cap-189, step h(Enantiomer-1; 300 mg) and Cap-189, step h (Enantiomer-2; 310 mg) aswhite solids. Cap-189, step h (Enantiomer-1): LC-MS: Anal. Calcd. for[M+H]⁺ C₁₈H₂₂NO₅ 332.15. found 332.2. ¹H NMR (500 MHz, CDCl₃) δ ppm7.29-7.41 (5H, m), 6.00 (1H, br. s.), 5.13 (2H, s), 3.63-3.87 (8H, m),2.84 (1H, br. s.), 1.84-2.02 (2H, m), 1.63-1.84 (2H, m). Cap-189, step h(Enantiomer-2): LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₂NO₅ 332.15. found332.2.

N₂ was bubbled through a solution of Cap-189, step h (Enantiomer-2; 290mg, 0.875 mmol) in 10 mL of MeOH in a 500 mL hydrogenation bottle for 30mins. To the solution was added (S,S)-Me-BPE-Rh (9.74 mg, 0.018 mmol),and the mixture was then hydrogenated at 60 psi for 6 days. The mixturewas concentrated, and chiral analytical HPLC (CHIRALPAK® OJ column)indicated that there were a small amount of remaining starting materialand one major product. The residue was then separated by chiral HPLC(CHIRALPAK® OJ column, 21×250 mm, 10 um) eluting with 70% 0.1%diethylamine/Heptane-30% EtOH at 15 mL/min to afford Cap-189, step i,(150 mg) as clear oil. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₄NO₅ 334.17.found 334.39. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.28-7.41 (5H, m), 5.12-5.18(1H, m), 5.09 (2H, s), 4.05 (1H, t, J=10.07 Hz), 3.75 (3H, s), 3.60-3.72(2H, m), 3.41-3.50 (2H, m), 2.10 (1H, br. s.), 1.72-1.99 (6H, m).

To a solution of Cap-189, step i (150 mg, 0.450 mmol) in 10 mL of MeOHin a hydrogenation bottle were added dimethyl dicarbonate (0.072 mL,0.675 mmol) and 10% Pd/C (23.94 mg, 0.022 mmol) under a cover ofnitrogen cover. The mixture was then hydrogenated on Parr-shaker at 45psi overnight. The mixture was filtered and the filtrate wasconcentrated to afford Cap-189, step j (110 mg) as a clear oil. LC-MS:Anal. Calcd. for [M+H]⁺ C₁₂H₂₀NO₅ 258.13. found 258.19. ¹H NMR (500 MHz,CDCl₃) δ ppm 5.08 (1H, d, J=9.16 Hz), 4.03 (1H, t, J=10.07 Hz), 3.75(3H, s), 3.60-3.72 (5H, m), 3.46 (2H, t, J=10.38 Hz), 2.11 (1H, br. s.),1.72-1.99 (6H, m).

Cap-189

To a mixture of Cap-189, step j (110 mg, 0.428 mmol) in 2 mL of THF and1 mL of water was added LiOH (0.641 mL, 1.283 mmol) (2 N aq.). Theresulting mixture was stirred at room temperature overnight. The mixturewas neutralized with a 1 N HCl aq. solution and extracted with EtOAc(3×). The combined organic layers were dried with MgSO₄ and concentratedto afford Cap-189 (100 mg) as a white solid. LC-MS: Anal. Calcd. for[M+Na]⁺ C₁₁H₁₇NNaO₅ 266.10. found 266.21. ¹H NMR (500 MHz, CDCl₃) δ ppm5.10 (1H, d, J=9.16 Hz), 4.02 (1H, t, J=10.07 Hz), 3.62-3.78 (5H, m),3.49 (2H, d, J=10.68 Hz), 2.07-2.22 (2H, m), 1.72-1.98 (6H, m).

To a mixture of cyclopent-3-enol (2.93 g, 34.8 mmol) and imidazole (5.22g, 77 mmol) in 30 mL of DMF at 0° C. was addedt-butyldimethylchlorosilane (6.30 g, 41.8 mmol). The resulting colorlessmixture was stirred at room temperature overnight. Hexanes and waterwere then added to the mixture and the two layers were separated. Theaqueous layer was extracted with EtOAc (2×) and the combined organiclayers were washed with brine, dried with MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (silica gel, 2%EtOAc/Hex) to afford Cap-190, step a (6.3 g) as a clear oil. ¹H NMR (500MHz, CDCl₃) δ ppm 5.65 (2H, s), 4.49-4.56 (1H, m), 2.56 (2H, dd,J=15.26, 7.02 Hz), 2.27 (2H, dd, J=15.26, 3.36 Hz), 0.88 (9H, s), 0.06(6H, s).

To a solution of Cap-190, step a (2.3 g, 11.59 mmol) in 40 mL of CH₂Cl₂at 0° C. was added m-CPBA (5.60 g, 16.23 mmol) in 5 portions. Thereaction mixture was stirred at room temperature overnight. Hexanes andwater were then added to the mixture and the two layers were separated.The organic layer was washed with 50 mL aq. 10% NaHSO₃ and brine, driedwith MgSO₄ and concentrated. The crude product was purified by flashchromatography (silica gel, 3%-6% EtOAc/Hex) to afford Cap-190, step b(1.42 g) and its trans diastereomer (0.53 g) as clear oils. Cap-190,step b (cis): ¹H NMR (400 MHz, CDCl₃) δ ppm 4.39-4.47 (1H, m), 3.47 (2H,s), 2.01-2.10 (2H, m), 1.93-2.00 (2H, m), 0.88 (9H, s), 0.04 (6H, s).Cap-190, step b (trans): ¹H NMR (400 MHz, CDCl₃) δ ppm 4.04-4.14 (1H,m), 3.47 (2H, s), 2.41 (2H, dd, J=14.05, 7.28 Hz), 1.61 (2H, dd,J=14.18, 6.90 Hz), 0.87 (9H, s), 0.03 (6H, s).

To a solution of (S)-1,2′-methylenedipyrrolidine (0.831 g, 5.39 mmol) in15 mL of benzene at 0° C. was added dropwise n-butyllithium (4.90 mL,4.90 mmol) (1 M in hexane). The solution turned bright yellow. Themixture was stirred at 0° C. for 30 min. Cap-190, step b (cis-isomer;0.7 g, 3.27 mmol) in 10 mL of benzene was then added and the resultingmixture was stirred at 0° C. for 3 hours. EtOAc and sat. NH₄Cl aq.solution were added into the mixture, and the two layers were separated.The organic layer was washed with water and brine, dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 15% EtOAc/Hex) to afford Cap-190, step c (400 mg) as alight yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.84-5.98 (2H, m),4.53-4.69 (2H, m), 2.63-2.73 (1H, m), 1.51 (1H, dt, J=13.73, 4.43 Hz),0.89 (9H, s), 0.08 (6H, s).

To a solution of Cap-190, step c (400 mg, 1.866 mmol), MeI (1.866 mL,3.73 mmol) (2 M in t-butyl methyl ether) in 5 mL of THF at 0° C. wasadded NaH (112 mg, 2.80 mmol) (60% in mineral oil). The resultingmixture was allowed to warm up to room temperature and stirred at roomtemperature overnight. The reaction was then quenched with water andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried with MgSO₄ and concentrated. The crude product was purifiedby flash chromatography (silica gel, 5% EtOAc/Hex) to afford Cap-190,step d (370 mg) as light yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm5.92-5.96 (1H, m), 5.87-5.91 (1H, m), 4.64-4.69 (1H, m), 4.23-4.28 (1H,m), 3.32 (3H, s), 2.62-2.69 (1H, m), 1.54 (1H, dt, J=13.12, 5.49 Hz),0.89 (9H, s), 0.07 (5H, d, J=1.83 Hz).

To a solution of Cap-190, step d (400 mg, 1.751 mmol) in 10 mL of EtOAcin a hydrogenation bottle was added platinum(IV) oxide (50 mg, 0.220mmol). The resulting mixture was hydrogenated at 50 psi on Parr shakerfor 2 hours. The mixture was then filtered through CELITE®, and thefiltrate was concentrated to afford Cap-190, step e (400 mg) as a clearoil. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₂₇O₂Si 231.18. found 231.3. ¹HNMR (500 MHz, CDCl₃) δ ppm 4.10-4.17 (1H, m), 3.65-3.74 (1H, m), 3.27(3H, s), 1.43-1.80 (6H, m), 0.90 (9H, s), 0.09 (6H, s).

To a solution of Cap-190, step e (400 mg, 1.736 mmol) in 5 mL of THF wasadded TBAF (3.65 mL, 3.65 mmol) (1 N in THF). The color of the mixtureturned brown after several min., and it was stirred at room temperatureovernight. The volatile component was removed under vacuum, and theresidue was purified by flash chromatography (silica gel, 0-25%EtOAc/Hex) to afford Cap-190, step f (105 mg) as light yellow oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 4.25 (1H, br. s.), 3.84-3.92 (1H, m), 3.29(3H, s), 1.67-2.02 (6H, m).

Cap-190

Cap-190 was then synthesized from Cap-190, step f according to theprocedure described for Cap-182. LC-MS: Anal. Calcd. for [M+Na]⁺C₁₀H₁₇NNaO₅ 254.10. found 254.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.25 (1H,d, J=8.55 Hz), 4.27-4.41 (1H, m), 3.81-3.90 (1H, m), 3.69 (3H, s), 3.26(3H, s), 2.46-2.58 (1H, m), 1.76-1.99 (3H, m), 1.64-1.73 (1H, m),1.40-1.58 (1H, m), 1.22-1.38 (1H, m).

To a solution of diisopropylamine (3 ml, 21.05 mmol) in THF (3 ml) at−78° C. under nitrogen was added n-butyl lithium (2.5 M in hexanes; 8.5ml, 21.25 mmol). The reaction was stirred at −78° C. for 10 min thenbrought up to 0° C. for 25 min. The reaction was cooled down again to−78° C., methyl tetrahydro-2H-pyran-4-carboxylate (3 g, 20.81 mmol) inTHF (3 ml) was added. The reaction was stirred at −78° C. for 15 minthen brought up to 0° C. for 30 min. The reaction was cooled down to−78° C., methyl iodide (1.301 ml, 20.81 mmol) was added. After theaddition, the cold bath was removed and the reaction was allowed toslowly warm up to ˜25° C. and stirred for 22 h. Ethyl acetate andaqueous HCl (0.1N) were added, and the organic layer was separated andwashed with brine and dried (MgSO₄), filtered, and concentrated invacuo. The residue was loaded on a Thomson's silica gel cartridgeeluting with 10% ethyl acetate/hexanes to afford a light yellow oil(2.83 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.73-3.66 (m, 2H), 3.66 (s,3H), 3.40-3.30 (m, 2H), 1.95-1.93 (dm, 1H), 1.92-1.90 (dm, 1H), 1.43(ddd, J=13.74, 9.72, 3.89, 2H), 1.18 (s, 3H).

To a solution of Cap-191, step a (3 g, 18.96 mmol) in toluene (190 ml)at −78° C. under nitrogen was added diisobutylaluminum hydride (1.5M intoluene; 26.5 ml, 39.8 mmol) dropwise. The reaction was continued tostir at −78° C. for 1.5 h., and the bath was removed and was stirred for18 h. The reaction was quenched with MeOH (20 mL). HCl (1M, 150 mL) wasadded and the mixture was extracted with EtOAc (4×40 mL). The combinedorganic phases were washed with brine, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified with flashchromatography (silica gel; 40% ethyl acetate/hexanes) to afford acolorless oil (1.36 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.77 (dt, J=11.73,4.55, 2H), 3.69-3.60 (m, 2H), 3.42 (s, 2H), 1.71-1.40 (bs, 1H) 1.59(ddd, J=13.74, 9.72, 4.39, 2H), 1.35-1.31 (m, 1H), 1.31-1.27 (m, 1H),1.06 (s, 3H).

To a solution of DMSO (5.9 ml, 83 mmol) in CH₂Cl₂ (85 ml) at −78° C.under nitrogen was added oxalyl chloride (3.8 ml, 43.4 mmol) and stirredfor 40 min. A solution of Cap-191, step b (4.25 g, 32.6 mmol) in CH₂Cl₂(42.5 ml) was then added. The reaction was continued to be stirred at−78° C. under nitrogen for 2 h. The reaction was quenched with cold 20%K₂HPO₄ (aq) (10 mL) and water. The mixture was stirred at ˜25° C. for 15min, diluted with diethyl ether (50 mL) and the layers were separated.The aqueous layer was extracted with diethyl ether (2×50 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and concentrated in vacuo. The residue was taken up in CH₂Cl₂ (4 mL) andpurified with flash chromatography (silica gel, eluting with CH₂Cl₂) toafford a colorless oil (2.1 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.49 (s.1H), 3.80 (dt, J=11.98, 4.67, 2H), 3.53 (ddd, J=12.05, 9.41, 2.89, 2H),1.98 (ddd, J=4.71, 3.20, 1.38, 1H), 1.94 (ddd, J=4.71, 3.20, 1.38, 1H),1.53 (ddd, J=13.87, 9.60, 4.14, 2H), 1.12 (s, 3H).

To a solution of Cap 191c (2.5 g, 19.51 mmol) in CHCl₃ (20 ml) undernitrogen at ˜25° C. was added (R)-2-amino-2-phenylethanol (2.94 g, 21.46mmol) and stirred for 5 h. The reaction was cooled to 0° C.,trimethylsilyl cyanide (3.8 ml, 30.4 mmol) was added dropwise. The coldbath was removed and the reaction was allowed to stir at ˜25° C. undernitrogen for 15.5 h. The reaction was treated with 3N HCl (20 mL) andwater (20 mL), and the product was extracted with CHCl₃ (3×50 mL). Thecombined organic layers were dried (NaSO₄), filtered, and concentratedin vacuo. The residue was purified with flash chromatography (silicagel; 40% ethyl acetate/hexanes) to afford two diastereomers: Cap-191,step d1 (diastereomer 1) as a colorless oil which solidified into awhite solid upon standing (3 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.42-7.26 (m, 5H), 5.21 (t, J=5.77, 1H), 3.87 (dd, J=8.53, 4.52, 1H),3.61-3.53 (m, 1H), 3.53-3.37 (m, 5H), 3.10 (d, J=13.05, 1H), 2.65 (d,J=13.05, 1H), 1.64-1.55 (m, 1H), 1.55-1.46 (m, 1H), 1.46-1.39 (m, 1H),1.31-1.23 (m, 1H), 1.11 (s, 3H). LC-MS: Anal. Calcd. for [M+H]⁺C₁₆H₂₃N₂O₂: 275.18. found 275.20. Cap-191, step d2 (diastereomer 2) as alight yellow oil (0.5 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.44-7.21 (m,5H), 4.82 (t, J=5.40, 1H), 3.82-3.73 (m, 1H), 3.73-3.61 (m, 3H),3.61-3.37 (m, 5H), 2.71 (dd, J=9.29, 4.77, 1H), 1.72-1.55 (m, 2H),1.48-1.37 (m, 1H), 1.35-1.25 (m, 1H), 1.10 (s, 3H). LC-MS: Anal. Calcd.for [M+H]⁺ C₁₆H₂₃N₂O₂: 275.18. found 275.20.

To a solution of Cap-191, step d2 (diastereomer 2) (0.4472 g, 1.630mmol) in CH₂Cl₂ (11 ml) and MeOH (5.50 ml) at 0° C. under nitrogen wasadded lead tetraacetate (1.445 g, 3.26 mmol). The reaction was stirredfor 1.5 h, the cold bath was removed and stirring was continued for 20h. The reaction was treated with a phosphate buffer (pH=7; 6 mL) andstirred for 45 min. The reaction was filtered over CELITE®, washed withCH₂Cl₂ and the layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (3×25 mL), and the combined organic layers was washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified with flash chromatography (silica gel; 15% ethylacetate/hexanes) to afford the imine intermediate as a colorless oil(181.2 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (d, J=1.00, 1H),7.89-7.81 (m, 2H), 7.61-7.46 (m, 3H), 4.80 (d, J=1.00, 1H), 3.74 (tt,J=11.80, 4.02, 2H), 3.62-3.46 (m, 2H), 1.79-1.62 (m, 2H), 1.46-1.30 (m,2H), 1.15 (s, 3H).

The imine intermediate was taken up in 6N HCl (10 mL) and heated at 90°C. for 10 days. The reaction was removed from the heat, allowed to coolto room temperature and extracted with ethyl acetate (3×25 mL). Theaqueous layer was concentrated in vacuo to afford an off-white solid.The solid was taken up in MeOH and loaded on a pre-conditioned MCX (6 g)cartridge, washed with MeOH followed by elution with 2N NH₃/MeOHsolution and concentrated in vacuo to afford an off-white solid (79.8mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 14.33-13.51 (bs, 1H), 8.30 (bs,3H), 3.82-3.75 (m, 1H), 3.70 (dt, J=11.80, 4.02, 2H), 3.58-3.43 (m, 2H),1.76-1.60 (m, 2H), 1.47-1.36 (m, 1H), 1.36-1.27 (m, 1H), 1.08 (s, 3H).LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₁₆NO₃: 174.11. found 174.19.

Cap-191 (Enantiomer-1)

To a solution of Cap-191, step e (0.0669 g, 0.386 mmol) and sodiumcarbonate (0.020 g, 0.193 mmol) in sodium hydroxide (1M aq.; 0.4 ml,0.40 mmol) at 0° C. was added methyl chloroformate (0.035 ml, 0.453mmol) dropwise. The reaction was removed from the cold bath and allowedto stir at ˜25° C. for 3 h. The reaction was washed with diethyl ether(3×20 mL). The aqueous layer was acidified with 12 N HCl (pH˜1-2), andextracted with ethyl acetate (2×20 mL). The combined organic layers weredried (MgSO₄), filtered, and concentrated in vacuo to afford Cap-191 asa colorless film (66.8 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.10-12.37(bs, 1H), 7.37 (d, J=9.04, 1H), 4.02 (d, J=9.29, 1H), 3.72-3.57 (m, 2H),3.56 (s, 3H), 3.54-3.44 (m, 2H), 1.65 (ddd, J=13.61, 9.72, 4.27, 1H),1.53 (ddd, J=13.68, 9.66, 4.27, 1H), 1.41-1.31 (m, 1H), 1.31-1.22 (m,1H), 1.00 (s, 3H). LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₀H₁₇NO₅Na: 254.10.found 254.11.

Cap-192 (Enantiomer-2) was prepared from Cap-191, step d1 according tothe procedure described for the preparation of its enantiomer Cap-191.

Intermediates

Literature ChemComm, 21722174 (2005). Mixture of Intermediate 12,6-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene AndIntermediate 22,7-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene

To a degassed solution of naphthalene (19.34 g, 151 mmol) andbis(pinacolato)diboron (84 g, 330 mmol) in cyclohexane (500 mL) wasadded 4,4′-di-tert-buthyl-2,2′-dipyridyl (4.05 g, 15.1 mmol) anddi-μ-methoxybis(1,5-cyclooctadiene)diirridium (I) (5.0 g, 7.5 mmol). Theflask was sealed and heated at 80° C. for 16 h then allowed to cool toroom temperature. The reaction color turned dark red upon heating. Thevolatile component was removed in vacuo and the resulting material waspurified with flash chromatography (sample was dry loaded on silica geland eluted with 0-100% ethyl acetate/toluene) to afford a mixture of2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene and2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (54.57g, 95% yield, 1.5:1 ratio) as white solid.

Intermediate 1: ¹H NMR (500 MHz, benzene-d₆) δ ppm 8.70 (s, 2H), 8.16(d, J=8.2 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 1.15 (s, 24H).

Intermediate 2: ¹H NMR (500 MHz, benzene-d₆) δ ppm 8.77 (s, 2H), 8.22(d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H). 1.15 (s, 24H).

Mixture of Intermediate 3 (2S,2′S)-tert-Butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylateAnd Intermediate 4 (2S,2′S)-tert-Butyl2,2′-(5,5′-(naphthalene-2,7-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

To a mixture of2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene and2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (1.5:1)(1.25 g, 3.29 mmol) and (S)-tert-butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (3.01 g,8.22 mmol) in 1,2-dimethoxyethane (50 mL) and water (12.5 mL) was addedNaHCO₃ (1.38 g, 16.4 mmol). The reaction mixture was degassed in vacuoand flushed with nitrogen. Pd(Ph₃P)₄ (190 mg, 0.164 mmol) was added andthe pressure flask was capped and heated with an oil bath at 85° C. for16 hours. The volatile component was removed in vacuo. The residue waspartitioned between ethyl acetate and water. The layers were separatedand the aqueous phase was extracted several times with ethyl acetate.The combined organic phases were filtered through a pad of diatomaceousearth (CELITE®) and the filtrate was dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting material was purified with flashchromatography (sample was dry loaded on silica gel and eluted with10-100% ethyl acetate/CH₂Cl₂) then flushed with (10% methanol/CH₂Cl₂) toafford a mixture of (2S,2′S)-tert-butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylateand (2S,2′S)-tert-butyl2,2′-(5,5′-(naphthalene-2,7-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(622 mg, 27.1% yield) as orange solid which was used without furtherpurification. An aliquot was purified by a reverse phase HPLC(water/acetonitrile/TFA) to provide an analytical sample of eachintermediate as a TFA salt.

Analytical data for Intermediate 3: LC-MS retention time 1.46 min;calcd. for C₄₂H₄₆N₆O₄: 698.36. found m/z 699.26 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.28 (br s, 2H), 8.13 (t, J=8.7 Hz,4H), 8.05 (t, J=8.4 Hz, 2H), 7.92 (dd, J=14.8, 8.7 Hz, 3H), 5.20-5.36(m, 2H), 3.70-3.84 (m, 2H), 3.57-3.70 (m, 2H), 2.54-2.70 (m, 2H),2.18-2.28 (m, 2H), 2.14 (quin, J=6.9 Hz, 4H), 1.50 (s, 9H), 1.23 (s,9H).

Analytical data for Intermediate 4: LC-MS retention time 1.52 min;calcd. for C₄₂H₄₆N₆O₄: 698.36. found m/z 699.24 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.33 (br s, 2H), 7.98-8.17 (m, 6H),7.83-7.98 (m, 4H), 5.18-5.35 (m, 2H), 3.71-3.83 (m, 2H), 3.57-3.70 (m,2H), 2.63 (br s, 2H), 2.19-2.28 (m, 2H), 2.07-2.18 (m, 4H), 1.50 (s,9H), 1.22 (s, 9H).

Mixture of Intermediate 5 (S)-tert-Butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylatetrifluoroacetate And Intermediate 6 (S)-tert-Butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylatetrifluoroacetate

After flash chromatography purification, the above reaction alsoprovided a mixture of (S)-tert-butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylatetrifluoroacetate and (S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(658 mg). During the HPLC separation (TFA buffer) the boronic esterspartially hydrolyzed to afford the same mixture as boronic acidintermediates. LC-MS retention time 1.34 min (boronic acids) and 2.05(boronic esters); calcd. for (boronic acids) C₂₆H₂₈BN₃O₄: 457.22 Foundm/z 458.14 [M+H]⁺. For (boronic esters) [M+H]⁺ C₃₂H₃₈BN₃O₄: 539.3. foundm/z 490.16 [M]⁺. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min and an analysis time of 4 min whereSolvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA.

Intermediate 72,6-Bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene andIntermediate 82,7-Bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene

A mixture of (2S,2′S)-tert-butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylateand (2S,2′S)-tert-butyl2,2′-(5,5′-(naphthalene-2,7-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(594 mg, 0.162 mmol) and TFA (2 mL) in CH₂Cl₂ (10 mL) was stirred atambient conditions for 3 hours. The volatile component was removed invacuo and the crude material was purified by a reverse phase HPLC(water/acetonitrile/TFA) to provide a TFA salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(434 mg) as yellow solid and a TFA salt of2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(204.8 mg) as yellow solid.

Analytical data for Intermediate 7: LC-MS retention time 1.05 min;calcd. for C₃₂H₃₀N₆ 498.25. found m/z 499.21 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.00 (s,1H), 7.84-7.92 (m, 1H), 7.73-7.81 (m, 2H), 5.08 (t, J=7.6 Hz, 1H),3.56-3.66 (m, 1H), 3.48-3.56 (m, 1H), 2.62-2.71 (m, 1H), 2.36-2.47 (m,1H), 2.19-2.36 (m, 2H).

Analytical data for Intermediate 8: LC-MS retention time 1.11 min;calcd. for C₃₂H₃₀N₆ 498.25 Found m/z 499.20 [M+H]⁺. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a WatersSunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.23 (s, 2H), 8.01 (m, 4H), 7.82-7.89 (m, 2H),7.69-7.82 (m, 4H), 5.08 (t, J=7.6 Hz, 2H), 3.57-3.66 (m, 2H), 3.48-3.57(m, 2H), 2.60-2.73 (m, 2H), 2.37-2.48 (m, 2H), 2.19-2.36 (m, 4H).

(S)-tert-Butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Glyoxal (2.0 mL of 40% in water) was added dropwise over 11 minutes to amethanol solution of NH₄OH (32 mL) and (S)-Boc-prolinal (8.56 g, 43.0mmol) and the reaction was stirred at ambient temperature for 19 hours.The volatile component was removed in vacuo and the residue was purifiedby a flash chromatography (silica gel, ethyl acetate) followed by arecrystallization (ethyl acetate, room temperature) to provide(S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate as a whitefluffy solid (4.43 g, 18.6 mmol, 43% yield). ¹H NMR (DMSO-d₆, 400 MHz) δppm 11.68/11.59 (br s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 4.76 (m, 1H),3.48 (m, 1H), 3.35-3.29 (m, 1H), 2.23-1.73 (m, 4H), 1.39/1.15 (s, 9H).LC-MS. RT=0.87 min; >95% homogeneity index; LC-MS: Anal. Calcd. for[M+H]⁺ C₁₂H₂₀N₃O₂ 238.16. found 238.22. The compound shown to have a98.9 ee % when analyzed under the chiral HPLC conditions noted below.Column: CHIRALPAK® AD, 10 um, 4.6×50 mm

Solvent: 1.7% ethanol/heptane (isocratic)Flow rate: 1 mL/minWavelength: either 220 or 256 nmRelative retention time: 3.25 min (R), 5.78 minutes (S)

(S)-tert-Butyl 2-(4,5-diiodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Iodine (16.17 g, 63.7 mmol) was added to a solution of (S)-tert-butyl2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate (6.87 g, 29.0 mmol) andsodium carbonate (9.21 g, 87 mmol) in dioxane (72 mL) and water (72 mL)at ambient temperature. The flask was covered with aluminum foil andstirrer for 16 hours. The reaction mixture was diluted with ethylacetate and a saturated aqueous solution of sodium thiosulfate. Themixture was stirred for 15 minutes and the phases were separated. Theaqueous phase was extracted several times with ethyl acetate. Thecombined organic phases were dried (Na₂SO₄), filtered and concentratedin vacuo to afford (S)-tert-butyl2-(4,5-diiodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (12.5 g 88%) asa tan solid. LC-MS retention time 1.40 min; calcd. for C₁₂H₁₇I₂N₃O₂488.94. found m/z 489.96 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters Sunfire 5 u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 4.72-4.84 (m, 1H), 3.58-3.70 (m, 1H),3.43-3.54 (m, 1H), 2.36 (br s, 1H), 1.88-2.08 (m, 3H), 1.47 (br s, 3H),1.27 (br s, 6H).

(S)-tert-Butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Sodium sulfite (10.31 g, 82 mmol) was added to a solution of(S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(4.0 g, 8.2 mmol) in ethanol (75 mL) and water (75 mL). The suspensionwas heated with an oil bath at 100° C. for 4 hours and at 90° C. for 16h. The reaction was diluted with ethyl acetate and water. The layerswere separated and the aqueous layer was extracted several times withethyl acetate. The combined organic phases were dried (brine, Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by a flashchromatography (sample was dry loaded on silica gel and eluted with, 0to 40% ethyl acetate/CH₂Cl₂) to afford (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.17 g, 73.1%) asa white solid. LC-MS retention time 0.930 min; calcd. for C₁₂H₁₈1 N₃O₂363.04. found m/z 364.06 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters Sunfire 5 u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 7.52-7.64 (m, 1H), 4.95-5.10 (m, 1H),3.57-3.70 (m, 1H), 3.47-3.57 (m, 1H), 2.37-2.55 (m, 1H), 1.94-2.10 (m,3H), 1.46 (s, 4H), 1.27 (s, 5H).

Mixture of Intermediate 12 (S)-tert-Butyl2-(5-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateAnd Intermediate 13 (S)-tert-Butyl2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a mixture of (S)-tert-butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylatetrifluoroacetate and (S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylatetrifluoroacetate (560 mg, 0.980 mmol) and (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (463 mg, 1.27 mmol)in 1,2-dimethoxyethane (11.2 mL) and water (2.8 mL) was added NaHCO₃(412 mg, 4.90 mmol). The reaction mixture was degassed in vacuo for 5minutes and was flushed with nitrogen. Pd(Ph₃P)₄ (57 mg, 0.049 mmol) wasadded and the pressure flask was capped and heated with an oil bath at100° C. for 16 hours. The volatile component was removed in vacuo. Theresidue was partitioned between ethyl acetate and water and the aqueousphase was extracted several times with ethyl acetate. The combinedorganic phases were dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting material was purified with flash chromatography (samplewas dry loaded on silica gel and eluted with 50-100% ethylacetate/hexanes) to afford a partially purified mixture of productswhich was further purified by a reverse phase HPLC(water/acetonitrile/TFA) to provide a mixture of a TFA salt of(S)-tert-butyl2-(5-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand a TFA salt of (S)-tert-butyl2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(74 mg). LC-MS retention time 1.32 min; calcd. for [M+H]⁺ C₃₈H₄₄N₆O₄648.34. found m/z 649.20 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters Sunfire 5 u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA.The mixture was used without further purification.

Intermediate 142-((S)-Pyrrolidin-2-yl)-6-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazoleand Intermediate 152-((S)-Pyrrolidin-2-yl)-6-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-1H-benzo[d]imidazole

A mixture of (S)-tert-butyl2-(5-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand (S)-tert-butyl2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateas TFA salts (74 mg) and TFA (2 mL) in CH₂Cl₂ (10 mL) was stirred atambient conditions for 4 hours. The volatile component was removed invacuo. The crude material was purified by a reverse phase HPLC (0 to 50%water/acetonitrile/TFA) to provide a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazole(32 mg, 31%) as yellow oil and a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-1H-benzo[d]imidazole(16 mg) as yellow oil.

Analytical data for Intermediate 14: LC-MS retention time 0.081 min;calcd. for C₃₈H₂₈N₆ 448.24. found m/z 449.20 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.33 (s, 1H), 8.17 (s, 1H), 8.03 (d, J=3.7 Hz,1H), 8.01 (s, 2H), 7.92-7.97 (m, 1H), 7.87-7.92 (m, 1H), 7.75-7.80 (m,3H), 5.11 (t, J=7.8 Hz, 1H), 4.99 (t, J=7.9 Hz, 1H), 3.49-3.69 (m, 4H),2.56-2.76 (m, 2H), 2.41-2.52 (m, 2H), 2.21-2.41 (m, 4H).

Analytical data for Intermediate 15: LC-MS retention time 0.87 min;calcd. for C₃₈H₂₈N₆ 448.24. found m/z 449.21 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.39 (s, 1H), 8.19 (s, 1H), 7.97-8.04 (m, 3H),7.91 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.78 (s,2H), 5.12 (t, J=7.6 Hz, 1H), 5.04 (t, J=8.1 Hz, 1H), 3.50-3.68 (m, 4H),2.60-2.74 (m, 2H), 2.41-2.55 (m, 2H), 2.21-2.41 (m, 4H).

(S)-tert-Butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

EDCI.HCl (16.9 g, 88.0 mmol) was added to a mixture of4-bromobenzene-1,2-diamine (15.0 g, 80.0 mmol), N-Boc-L-proline (18.13g, 84.0 mmol) and 1-hydroxybenzotriazole (12.28 g, 80.0 mmol) in CH₂Cl₂(500 mL) and stirred at ambient conditions for 16 h. The mixture wasthen diluted with water. The resulting white precipitate was filteredaway and the layers were separated. The organic layer was washed withwater, dried (brine; Na₂SO₄), filtered and concentrated in vacuo toprovide a brown foam. Acetic acid (300 mL) was added to the foam and themixture was heated at 85° C. (bath temperature) for 5 h. The volatilecomponent was removed in vacuo and the residue was dissolved in EtOAc,washed with water and the organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo. The resultant crude material was submitted toflash chromatography (silica gel; 0-37% EtOAc/CH₂Cl₂). The partiallypure material was re-submitted to flash chromatography (silica gel;20-35% EtOAc/CH₂Cl₂) to provide (S)-tert-butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (17.98 g,61.2% yield) as yellow foam. LC-MS retention time 1.23 min; calcd. forC₁₆H₂₀BrN₃O₂: 365.07. found m/z 368.07 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (500 MHz, MeOD) δ ppm 7.59-7.75 (m., 1H), 7.38-7.53 (m,1H), 7.31-7.38 (m, 1H), 5.04-5.09 (m, 0.3H), 4.94-5.00 (m, 0.7H),3.68-3.76 (m, 1H), 3.50-3.59 (m, 1H), 2.34-2.51 (m., 1H), 1.95-2.12 (m.,3H), 1.47 (br s, 3H), 1.15 (s, 6H).

(S)-tert-Butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a flask containing a mixture of (S)-tert-butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (4.5 g, 12mmol) and bis(pinacolato)diboron (6.55 g, 25.8 mmol) in 1,4-dioxane (50mL) was added potassium acetate (3.01 g, 30.7 mmol). The reaction flaskwas degassed in vacuo for 5 minutes and then purged with nitrogen. Thecatalyst Pd(Ph₃P)₄ (710 mg, 0.614 mmol) was added and the flask wascapped and heated with an oil bath at 85° C. (bath temperature) for 16h. The reaction mixture was concentrated in vacuo. The crude materialwas partitioned between CH₂Cl₂ and a saturated NaHCO₃ solution and theaqueous layer was extracted with CH₂Cl₂. The combined organic phase wasdried (brine, Na₂SO₄), filtered and concentrated in vacuo. The resultingmaterial was purified with flash chromatography (sample was dry loadedon silica gel and eluted with 10-50% ethyl acetate/CH₂Cl₂) to provide(S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(2.80 g, 55% yield) as white solid. LC-MS retention time 1.493 min;calcd. for C₂₂H₃₂BN₃O₄: 413.25. found m/z 414.23 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (400 MHz, MeOD) δ ppm 7.81-8.08 (m, 1H), 7.40-7.68 (m., 2H),4.95-5.13 (m, 1H), 3.68-0.3.79 (br s, 1H), 3.48-3.60 (br s, 1H),2.35-2.52 (br s, 1H), 1.95-2.15 (m, 3H), 1.46 (s, 3H), 1.37 (s, 12H),1.13 (s, 6H).

tert-Butyl2-(5-(6-(2-(1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate

To a mixture of (S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.29 g, 33.1 mmol) and 2,6-dibromonaphthalene (446 mg, 1.56 mmol) in1,2-dimethoxyethane (20 mL) and water (6 mL) was added NaHCO₃ (787 mg,9.36 mmol). The reaction mixture was degassed in vacuo for 10 minutesand was flushed with nitrogen. The catalyst Pd(Ph₃P)₄ (90 mg, 0.078mmol) was added and the flask was capped and heated with an oil bath at100° C. for 16 hours. The volatile component was removed in vacuo. Theresidue was partitioned between CH₂Cl₂ and water and the layers wereseparated. The aqueous phase was extracted several times with CH₂Cl₂ andthe combined organic phases were dried (brine, Na₂SO₄), filtered andconcentrated in vacuo. The resulting material was purified with flashchromatography (sample was dry loaded on silica gel and eluted with0-70% ethyl acetate/CH₂Cl₂) to afford tert-butyl2-(5-(6-(2-(1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate(605 mg) as yellow solid. LC-MS retention time 1.46 min; calcd. forC₄₂H₄₆N₆O₄: 698.36. found m/z 699.26 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA ¹HNMR (500 MHz, MeOD) δ ppm 8.28 (br s, 2H), 8.13 (t, J=8.7 Hz, 4H), 8.05(t, J=8.4 Hz, 2H), 7.92 (dd, J=14.8, 8.7 Hz, 4H), 5.20-5.36 (m, 2H),3.70-3.84 (m, 2H), 3.57-3.70 (m, 2H), 2.54-2.70 (m, 2H), 2.18-2.28 (m,2H), 2.14 (quin, J=6.9 Hz, 4H), 1.50 (s, 9H), 1.23 (s, 9H).

tert-Butyl(2S)-2-(5-(6-bromo-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate

The above reaction also provided tert-butyl(2S)-2-(5-(6-bromo-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate(519 mg) as yellow solid. LC-MS retention time 1.88 min; calcd. for[M+H]⁺ C₂₆H₂₆BrN₃O₂: 491.12. found m/z 494.04 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.21 (d, J=8.6 Hz, 1H), 8.05-8.14 (m, 2H),7.93-8.05 (m, 2H), 7.82-7.93 (m, 3H), 7.57-7.67 (m, 1H), 5.28 (br s,1H), 3.98 (s, 1H), 3.70-3.80 (m, 1H), 3.57-3.70 (m, 1H), 2.54-2.71 (m,1H), 2.17-2.29 (m, 1H), 2.09-2.17 (m, 2H), 1.49 (s, 4H), 1.22 (s, 5H).

5,5′-(2,6-Naphthalenediyl)bis(2-(2-pyrrolidinyl)-1H-benzimidazole)

A mixture of tert-butyl2-(5-(6-(2-(1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate(591 mg. 0.844 mmol) and TFA (2 mL) in CH₂Cl₂ (10 mL) was stirred atambient conditions for 2 hours. The volatile component was removed invacuo and the resulting material was loaded onto a MCX column, flushedwith methanol, released with 2.0 M NH₃/methanol elution) andconcentrated to provide5,5′-(2,6-naphthalenediyl)bis(2-(2-pyrrolidinyl)-1H-benzimidazole) (419mg) as tan solid. LC-MS retention time 1.02 min; calcd. for C₃₃H₃₁N₅:498.25. found m/z 499.25 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters Sunfire 5 u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.00 (s,1H), 7.84-7.92 (m, 1H), 7.73-7.81 (m, 2H), 5.08 (t, J=7.6 Hz, 1H),3.56-3.66 (m, 1H), 3.48-3.56 (m, 1H), 2.62-2.71 (m, 1H), 2.36-2.47 (m,1H), 2.19-2.36 (m, 2H).

2,6-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene

A pressure flask containing a mixture of 2,6-dibromonaphthalene (8.0 g,28 mmol), bis(pinacolato)diboron (21.3 g, 84.0 mmol), potassium acetate(3.01 g, 30.7 mmol) and 1,4-dioxane (50 mL) was degassed in vacuo for 5minutes and purged with nitrogen. The catalyst Pd(Ph₃P)₄ (710 mg, 0.614mmol) was added. The flask was capped and heated with an oil bath at 85°C. (bath temperature) for 16 hours. The reaction mixture wasconcentrated in vacuo and the crude material was partitioned betweenCH₂Cl₂ and a saturated NaHCO₃ solution. The aqueous layer was extractedwith CH₂Cl₂ and the combined organic phases was dried (Na₂SO₄), filteredand concentrated in vacuo. The resulting material was purified withflash chromatography (sample was dry loaded on silica gel and elutedwith 50-100% CH₂Cl₂/Hexanes) to provide2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalenecontaminated with bis(pinacolato)diboron. The solid was dissolved intoCH₂Cl₂ and methanol was added until precipitation was observed. Theprecipitate was collected by filtration to afford2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (5.1 g,48% yield) as white solid. ¹H NMR (500 MHz, benzene-d₆) δ ppm 8.70 (s,2H), 8.16 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 1.15 (s, 24H).

(2S,2′S)-tert-Butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate

To a mixture of2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (2.0 g,5.3 mmol) and (S)-tert-butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2.89 g,7.89 mmol) in 1,2-dimethoxyethane (42.1 mL) and water (10.5 mL) wasadded NaHCO₃ (2.21 g, 26.3 mmol). The reaction mixture was degassed invacuo and was flushed with nitrogen. The catalyst Pd(Ph₃P)₄ (90 mg,0.078 mmol) was added. The flask was capped and heated with an oil bathat 100° C. for 16 hours. The volatile component was removed in vacuo andthe residue was partitioned between ethyl acetate and water. The layerswere separated and the aqueous phase was extracted several times withethyl acetate. The combined organic phases were filtered through a padof diatomaceous earth (CELITE®) and the filtrate was dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting material was purifiedwith flash chromatography (sample was dry loaded on silica gel andeluted with 0-100% ethyl acetate/hexanes) to afford (2S,2′S)-tert-butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate(761 mg, 21% yield) as orange solid. LC-MS retention time 1.46 min;calcd. for C₄₂H₄₆N₆O₄: 698.36. found m/z 699.26 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA ¹HNMR (500 MHz, MeOD) δ ppm 8.28 (br s, 2H), 8.13 (t, J=8.7 Hz, 4H), 8.05(t, J=8.4 Hz, 2H), 7.92 (dd, J=14.8, 8.7 Hz, 4H), 5.20-5.36 (m, 2H),3.70-3.84 (m, 2H), 3.57-3.70 (m, 2H), 2.54-2.70 (m, 2H), 2.18-2.28 (m,2H), 2.09-2.19 (m, 4H), 1.50 (s, 9H), 1.23 (s, 9H).

(S)-tert-Butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

The above reaction also provided (S)-tert-butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.58 g, 56% yield) as tan solid. LC-MS retention time 1.46 min; calcd.for C₃₂H₃₈BN₃O₄: 539.3. found m/z 540.24 [M+H]⁺. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA.

(S)-5-((tert-Butyldiphenylsilyloxy)methyl)pyrrolidin-2-one

To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (10 g, 87 mmol)in CH₂Cl₂ (50 mL) was added tert-butylchlorodiphenylsilane (25.6 g, 93mmol), Et₃N (12.1 mL, 87 mmol) and DMAP (1.06 g, 8.7 mmol). The mixturewas stirred at room temperature until the starting pyrrolidinone wascompletely consumed and then diluted with CH₂Cl₂ (50 mL) and washed withwater (50 mL). The organic layer was dried (Na₂SO₄), filtered,evaporated in vacuo and the crude material was submitted to flashchromatography (silica gel; 30 to 100% of EtOAc/hexanes) to afford(S)-5-((tert-butyldiphenylsilyloxy)methyl)pyrrolidin-2-one (22.7 g, 74%yield) as a colorless oil. LC-MS (M+H)⁺=354.58. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.69 (br s, 1H), 7.64-7.61 (m, 4H), 7.50-7.42 (m, 6H),3.67-3.62 (m, 1H), 3.58-3.51 (m, 2H), 2.24-2.04 (m, 3H), 1.87-1.81 (m,1H), 1.00 (s, 9H).

(S)-tert-Butyl2-((tert-butyldiphenylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate

Di-tert-butyl dicarbonate (38.5 g, 177 mmol) was added in portions as asolid over 10 min to a solution of(S)-5-((tert-butyldiphenylsilyloxy)methyl)pyrrolidin-2-one (31.2 g, 88.3mmol), Et₃N (8.93 g, 88 mmol) and DMAP (1.08 g, 8.83 mmol) in CH₂Cl₂(200 mL) and the reaction mixture was stirred for 18 h at 24° C. Most ofthe volatile material was removed in vacuo and the crude material waspurified by silica gel chromatography (20% EtOAc/hexanes to 50%EtOAc/hexanes) to afford (S)-tert-butyl2-((tert-butyldiphenylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate(32.65 g, 82% yield) as a white solid. LC-MS (M-Boc+H)⁺=354.58. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.61-7.59 (m, 2H), 7.56-7.54 (m, 2H), 7.50-7.38(m, 6H), 4.18 (m, 1H), 3.90 (dd, J=10.4, 3.6, 1H), 3.68 (dd, J=10.4,2.1, 1H), 2.68-2.58 (m, 1H), 2.40-2.33 (m, 1H), 2.22-2.12 (m, 1H),2.01-1.96 (m, 1H), 1.35 (s, 9H), 0.97 (s, 9H).

(S)-tert-Butyl2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate

A three-necked flask equipped with a thermometer and a nitrogen inletwas charged with (S)-tert-butyl2-((tert-butyldiphenylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate(10.05 g, 22.16 mmol) and toluene (36 mL) and lowered into −55° C.cooling bath. When the internal temperature of the mixture reached −50°C., lithium triethylborohydride (23 mL of 1.0 M/THF, 23 mmol) was addeddropwise over 30 min and the mixture stirred for 35 min whilemaintaining the internal temperature between −50° C. and −45° C. Hunig'sbase (16.5 mL, 94 mmol) was added dropwise over 10 min. Then, DMAP (34mg, 0.278 mmol) was added in one batch, followed by the addition oftrifluoroacetic anhydride (3.6 mL, 25.5 mmol) over 15 min, whilemaintaining the internal temperature between −50° C. and −45° C. Thebath was removed 10 min later and the reaction mixture was stirred for14 h while allowing it to rise to ambient temperature. The reactionmixture was diluted with toluene (15 mL), cooled with an ice-water bathand treated slowly with water (55 mL) over 5 min. The phases wereseparated and the organic layer washed with water (50 mL, 2×) andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel; 5% EtOAc/hexanes) to afford (S)-tert-butyl2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate(7.947 g, 82% yield) as a colorless viscous oil. LC-MS: [M+Na]⁺=460.19.Rt=2.41 min under the following HPLC conditions: Solvent gradient from100% A: 0% B to 0% A: 100% B (A=0.1% TFA in 1:9 MeOH/water; B=0.1% TFAin 9:1 MeOH/water) over 2 min and hold for 1 min; detection at 220 nm;PHENOMENEX® Luna 3.0×50 mm S10 column. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.62-7.58 (m, 4H), 7.49-7.40 (m, 6H), 6.47 (br s, 1H), 5.07/5.01(overlapping br d, 1H), 4.18 (br s, 1H), 3.89 (br s, 0.5H), 3.69 (br s,1.5H), 2.90-2.58 (br m, 2H), 1.40/1.26 (overlapping br s, 9H), 0.98 (s,9H).

(3S)-tert-Butyl3-((tert-butyldiphenylsilyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Diethylzinc (19 mL of ˜1.1 M in toluene, 21 mmol) was added dropwiseover 15 min to a cooled (−30° C.) toluene (27 mL) solution of(S)-tert-butyl2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate(3.94 g, 9.0 mmol). Chloroiodomethane (stabilized over copper; 3.0 mL,41 mmol) was added dropwise over 10 min and stirred while maintainingthe bath temperature at −25° C. for 1 h and between −25° C. and −21° C.for 18.5 h. The reaction mixture was opened to the air and quenched bythe slow addition of 50% saturated NaHCO₃ solution (40 mL) and thenremoved from the cooling bath and stirred at ambient temperature for 20min. The reaction mixture was filtered through a filter paper and thewhite cake was washed with 50 mL of toluene. The organic phase of thefiltrate was separated and washed with water (40 mL, 2×), dried (MgSO₄)and concentrated in vacuo. The crude material was purified using bysilica gel chromatography (350 g silica gel; sample was loaded with 7%EtOAc/hexanes; eluted with 7-20% EtOAc/hexanes) to afford(3S)-tert-butyl3-((tert-butyldiphenylsilyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(3.69 g, 90.7%) as a mixture of cis/trans-isomers. [Note: the exactcis/trans-isomer ratio was not determined at this stage].LC-MS:[M+Na]⁺=474.14. Rt=2.39 min under the following HPLC conditions:Solvent gradient from 100% A:0% B to 0% A:100% B (A=0.1% TFA in 1:9MeOH/water; B=0.1% TFA in 9:1 MeOH/water) over 2 min and hold for 1 min;detection at 220 nm; PHENOMENEX® Luna 3.0×50 mm S10 column. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.62-7.60 (m, 4H), 7.49-7.40 (m, 6H), 3.77/3.67(overlapping br s, 3H), 3.11-3.07 (m, 1H), 2.23 (app br s, 1H),2.05-2.00 (m, 1H), 1.56-1.50 (m, 1H), 1.33 (very broad s, 9H), 1.00 (s,9H), 0.80 (m, 1H), 0.30 (m, 1H).

(3S)-tert-Butyl3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

TBAF (7.27 mL of 1.0 M in THF, 7.27 mmol) was added dropwise over 5 minto a THF (30 mL) solution of (3S)-tert-butyl3-((tert-butyldiphenylsilyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(mixture of cis/trans-isomers) (3.13 g, 6.93 mmol) and the mixture wasstirred at ambient temperature for 4.75 h. After the addition ofsaturated NH₄Cl solution (5 mL), most of the volatile material wasremoved in vacuo and the residue partitioned between CH₂Cl₂ (70 mL) and50% saturated NH₄Cl solution (30 mL). The aqueous phase was extractedwith CH₂Cl₂ (30 mL) and the combined organic phase was dried (MgSO₄),filtered, concentrated in vacuo and then exposed to high vacuumovernight. The crude material was purified using a flash chromatography(silica gel; 40-50% EtOAc/hexanes) to afford (3S)-tert-butyl3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.39 g, 94%yield) as a mixture of cis/trans-isomers and a colorless oil. [Note: theexact cis/trans-isomer ratio was not determined at this stage.] LC-MS(M+Na)⁺=236.20. ¹H NMR (400 MHz, DMSO-d₆, δ=2.5 ppm) δ ppm 4.70 (t,J=5.7, 1H), 3.62-3.56 (m, 1H), 3.49-3.44 (m, 1H), 3.33-3.27 (m, 1H),3.08-3.04 (m, 1H), 2.07 (br m, 1H), 1.93-1.87 (m, 1H), 1.51-1.44 (m,1H), 1.40 (s, 9H), 0.76-0.71 (m, 1H), 0.26 (m, 1H).

(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid

A semi-solution of NaIO₄ (6.46 g, 30.2 mmol) in water (31 mL) was addedto a solution of (3S)-tert-butyl3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (mixture ofcis/trans-isomers) (2.15 g, 10.08 mmol) in CH₃CN (20 mL) and CCl₄ (20mL). RuCl₃ (0.044 g, 0.212 mmol) was added immediately and theheterogeneous reaction mixture was stirred vigorously for 75 min. Thereaction mixture was diluted with water (60 mL) and extracted withCH₂Cl₂ (50 mL, 3×). The combined organic phases was treated with 1 mLMeOH, allowed to stand for about 5 min and then filtered through a padof diatomaceous earth (CELITE®). The pad was washed with CH₂Cl₂ (50 mL)and the filtrate was concentrated in vacuo to afford a lightcharcoal-colored solid. The crude material was dissolved in EtOAc (˜10mL) with heating and allowed to stand at ambient temperature withseeding. About 15 min into the cooling phase, a rapid crystal formationwas observed. About 1 h later, hexanes (˜6 mL) was added and the mixturerefrigerated overnight (it did not appear that additional materialprecipitated out). The mixture was filtered and washed withice/water-cooled hexanes/EtOAc (2:1 ratio; 20 mL) and dried under highvacuum to afford the first crop of(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (off-white crystals, 1.222 g). The mother liquor was concentratedin vacuo and the residue dissolved in ˜3 mL of EtOAc with heating,allowed to stand at ambient temperature for 1 h and then 3 mL hexaneswas added and stored in a refrigerator for ˜15 h. A second crop of(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid was retrieved similarly (grey crystals, 0.133 g), for a combinedyield of 59%. LC-MS [M+Na]⁺=250.22. Rt=1.48 min under the following HPLCconditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B (A=0.1%TFA in 1:9 methanol/water; B=0.1% TFA in 9:1 methanol/water) over 3 min;detection at 220 nm; PHENOMENEX® Luna 3.0×50 mm S10 column. MP (dec.)for the first crop=147.5-149.5° C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.46(s, 1H), 3.88 (app br s, 1H), 3.27 (app br s, 1H; overlapped with watersignal), 2.28 (br m, 1H), 2.07 (app br s, 1H), 1.56 (app s, 1H),1.40/1.34 (two overlapped s, 9H), 0.71 (m, 1H), 0.45 (m, 1H). 13C-NMR(100.6 MHz, DMSO-d₆) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88,59.58, 36.91, 31.97, 31.17, 27.77, 27.52, 14.86, 14.53, 13.69. Anal.Calcd. for C₁₁H₁₇NO₄: C, 58.13; H, 7.54; N, 6.16. Found (for firstcrop): C, 58.24; H, 7.84; N, 6.07. Optical rotation (10 mg/mL in CHCl₃):[α] D=−216 and −212 for the first and second crop, respectively.

An Alternative Synthesis for Intermediate 24:

(1R,3R,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxamide (.CH₃SO₃H) wasprepared according to the procedure described for the synthesis of itsstereoisomer in patent WO 2004/052850.

(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid

A 1 L round bottom flask equipped with a nitrogen inlet, overheadagitator, thermocouple and heating mantle was charged with 50 g (225mmol) (1R,3R,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxamide (.CH₃SO₃H) and250 mL isopropanol. The resulting slurry was then charged with 252 mL of23 wt % NaOEt in EtOH (2.68 M, 675 mmol, 3.0 equiv) and stirred at 50°C. for ca. 1 h. The mixture was charged with 12.2 mL (675 mmol, 3 equiv)of water and heated to 60° C. The resulting slurry was allowed to stirat 60° C. for ca. 18 h. The slurry was cooled to rt and charged with 250mL water and 98.2 g (450 mmol, 2.0 equiv) di-t-butyldicarbonate. Ethanoland isopropanol were removed via vacuum distillation and the aqueousmixture cooled to 0° C. The mixture was neutralized with 76 ml (456mmol) 6M aqueous HCl while maintaining an internal temperature <5° C.The product was extracted with 500 mL MTBE and the rich organic layerwas washed with 100 mL water. The clear solution was concentrated downto 150 mL via vacuum distillation and the resulting slurry was chargedwith 600 mL heptane while maintaining an internal temperature >45° C.The slurry was cooled to rt over ca. 30 min and allowed to stir at rtfor ca. 2 h. The product was filtered, washed with 250 mL 4:1heptane:MTBE and dried under vacuum at 70° C. to give 40.5 g (178 mmol,79% yield, 99.8 AP at 205 nm) of(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (s, 1H), 4.02-3.80 (m, 1H),3.45-3.15 (m, 1H), 2.40-2.19 (m, 1H), 2.19-2.0 (m, 1H), 1.70-1.50 (m,1H), 1.50-1.20 (m, 9H), 0.83-0.60 (m, 1H), 0.33-0.55 (m, 1H); ¹³C NMR(100 MHz, DMSO-d₆) δ 173.7, 173.2, 155.0, 154.3, 79.4, 60.5, 60.2, 37.6,32.6, 31.8, 28.4, 28.2, 15.6, 15.2, 14.4; HRMS calcd for C₁₁H₁₈NO₄ (M+H;ESI⁺): 228.1236. Found: 228.1234.

(1R,3S,5R)-tert-Butyl3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

EDCI.HCl (2.65 g, 13.8 mmol) was added to a mixture of4-bromobenzene-1,2-diamine 2.35 g, 12.6 mmol),(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (3.00 g, 13.2 mmol) and 1-hydroxybenzotriazole (1.93 g, 12.6 mmol)in CH₂Cl₂ (80 mL) and stirred at ambient conditions for 16 h. Themixture was then diluted with CH₂Cl₂, washed with water, dried (brine;MgSO₄), filtered and concentrated in vacuo to provide a brown foam.Acetic acid (80 mL) was added to the foam and the mixture was heated at75° C. (bath temperature) for 5 h. The volatile component was removed invacuo and the residue was dissolved in EtOAc, washed with saturatedNaHCO₃ solution and the organic phase was dried (brine; MgSO₄), filteredand concentrated in vacuo. The resultant crude material was submitted toflash chromatography (silica gel; 50-100% EtOAc/hexanes) to provide(1R,3S,5R)-tert-butyl3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(3.01 g, 7.96 mmol, 63.3% yield) as a light orange foam, which was usedwithout further purification. The reaction also yielded 847 mg of sameproduct with lower purity. An aliquot of the collected material waspurified further by preparative HPLC (C-18/30-100% CH₃CN-water+0.1%NH₄OAc) to achieve an analytical sample. LC-MS retention time 1.248 min;calcd. for C₁₇H₂₁BrN₃O₂: 378.08. found m/z 380.05 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (500 MHz, MeOD) δ ppm 7.67 (br s, 1H), 7.43 (br s, 1H),7.34 (d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 3.62 (br s, 1H), 2.50-2.57-2.31(m, 1H), 2.31 (dt, J=13.2, 6.7 Hz, 1H), 1.66-1.85 (m, 1H), 1.45 (br s,3H), 1.11 (br s, 6H), 0.87 (dt, J=8.6, 5.8 Hz, 1H), 0.66 (br s, 1H).

(1R,3S,5R)-tert-Butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a pressure flask containing a mixture of (1R,3S,5R)-tert-butyl3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.0 g, 5.3 mmol) and bis(pinacolato)diboron (2.69 g, 10.6 mmol) in1,4-dioxane (50 mL) was added potassium acetate (0.78 g, 7.9 mmol). Thereaction flask was degassed in vacuo for 10 min and purged withnitrogen. Pd(Ph₃P)₄ (305 mg, 0.264 mmol) was added to the reactionmixture and the flask was capped and heated with an oil bath at 85° C.(bath temperature) for 16 hours. The reaction mixture was concentratedin vacuo and the crude material was partitioned between CH₂Cl₂ (150 mL)and an aqueous medium (50 mL water+10 mL saturated NaHCO₃ solution). Theaqueous layer was extracted with CH₂Cl₂ and the combined organic phasewas dried (Na₂SO₄), filtered and concentrated in vacuo. The resultingmaterial was purified with flash chromatography (sample was dry loadedon silica gel and eluted with 20-100% ethyl acetate/hexanes) to provide(1R,3S,5R)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.74 g, 77% yield) as white foam. An aliquot of the collected materialwas further purified by preparative HPLC (C-18/30-100% CH₃CN-water+0.1%NH₄OAc). LC-MS retention time 1.78 min; calcd. for C₂₃H₃₂BN₃₂ 425.25.found m/z 426.21 [M+H]⁺. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 3 min, a hold time of 1 min and an analysis time of 4min where Solvent A was 5% acetonitrile/95% water/10 mmol ammoniumacetate and Solvent B was 95% acetonitrile/5% water/10 mmol ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode ¹H NMR (500 MHz, MeOD) δ ppm 7.94 (s, 1H), 7.61 (d,J=7.9 Hz, 1H), 7.41-7.56 (m, 1H), 4.83 (br s, 1H), 3.64 (d, J=1.2 Hz,1H), 2.51-2.70 (m, 1H), 2.33 (dt, J=13.4, 6.6 Hz, 1H), 1.67-1.84 (m,J=8.5, 6.10, 5.8, 5.8 Hz, 1H), 1.39-1.59 (br s, 3H), 1.37 (s, 12H), 1.10(br s, 6H), 0.88 (dt, J=8.2, 5.8 Hz, 1H), 0.66 (br s, 1H).

(1R,1′R,3S,3′S,5R,5′R)-tert-Butyl3,3′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-2-carboxylate)

To a mixture of (1R,3S,5R)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.50 g, 3.53 mmol) and 2,6-dibromonaphthalene (403 mg, 1.41 mmol) in1,2-dimethoxyethane (21.7 mL) and water (6.50 mL) was added NaHCO₃ (356mg, 4.23 mmol). The reaction mixture was degassed in vacuo for 10minutes and flushed with nitrogen. Pd(Ph₃P)₄ (82 mg, 0.071 mmol) wasadded and the reaction mixture was heated with an oil bath at 100° C.for 16 hours and then the volatile component was removed in vacuo. Theresidue was partitioned between CH₂Cl₂ and water (30 mL) and the aqueousphase was extracted several times with CH₂Cl₂. The combined organicphases were washed with brine, dried (Na₂SO₄), filtered and concentratedin vacuo. The resulting material was purified with flash chromatography(sample was dry loaded on silica gel and eluted with 0-70% ethylacetate/CH₂Cl₂) to afford (1R,1′R,3S,3′S,5R,5′R)-tert-butyl3,3′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-2-carboxylate)(377 mg) as yellow solid. LC-MS retention time 1.49 min; calcd. forC₄₄H₄₆N₆O₄: 722.36. found m/z 723.26 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (500 MHz, MeOD) δ ppm 8.26 (s, 2H), 8.12 (d, J=8.5 Hz, 2H),8.09 (s, 2H), 8.00 (m, J=8.6 Hz, 2H), 7.93 (m, J=8.6 Hz, 2H), 7.86 (d,J=8.6 Hz, 2H), 5.01 (br s, 2H), 3.68 (br s, 2H), 2.76 (dd, J=13.3, 9.3Hz, 2H), 2.42-2.54 (m, 2H), 1.87 (br s, 2H), 1.49 (br s, 9H), 1.19 (brs, 9H), 0.94 (dt, J=8.3, 6.1 Hz, 2H), 0.79 (br s, 2H).

(1R,3S,5R)-tert-Butyl3-(6-(6-bromonaphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

The above reaction also provided (1R,3S,5R)-tert-butyl3-(6-(6-bromonaphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(418 mg) as yellow solid. LC-MS retention time 1.90 min; calcd. forC₂₇H₂₆BrN₃O₂: 503.12. found m/z 506.05 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (500 MHz, MeOD) δ ppm 8.20 (s, 1H), 8.12 (s, 1H), 8.05 (s,1H), 7.93-8.00 (m, 2H), 7.86-7.93 (m, 2H), 7.84 (d, J=8.6 Hz, 1H), 7.63(dd, J=8.6, 1.8 Hz, 1H), 5.00 (br s, 1H), 3.68 (br s, 1H), 2.75 (dd,J=13.4, 9.2 Hz, 1H), 2.41-2.54 (m, 1H), 1.87 (br s, 1H), 1.49 (br s,5H), 1.17 (br s, 4H), 0.87-0.98 (m, 1H), 0.79 (br s, 1H).

2,6-Bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalene

A mixture of (1R,1′R,3S,3′S,5R,5′R)-tert-butyl3,3′-(6,6′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-2-carboxylate)(360 mg. 0.498 mmol) and TFA (2 mL) in CH₂Cl₂ (10 mL) was stirred atambient conditions for 3 hours. The volatile component was removed invacuo and the resulting material was loaded onto an MCX column, flushedwith methanol, eluted with 2.0 M NH₃/methanol and concentrated toprovide2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthaleneas yellow solid (253 mg). LC-MS retention time 1.07 min; calcd. forC₃₄H₃₀N₆: 522.25. found m/z 523.19 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (500 MHz, MeOD) δ ppm 8.17 (s, 2H), 8.06 (d, J=8.2 Hz, 2H),8.00 (s, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.71-7.81 (m, 4H), 4.84 (dd,J=10.8, 7.5 Hz, 2H), 3.47-3.53 (m, 2H), 2.80 (dd, J=12.8, 7.6 Hz, 2H),2.54-2.63 (m, 2H), 2.04-2.11 (m, 2H), 1.20-1.27 (m, 2H), 1.02 (q, J=7.7Hz, 2H).

Mixture of Intermediate 30 (S)-Benzyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatebistrifluoroacetate And Intermediate 31 (S)-Benzyl2-(5-(4-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatebistrifluoroacetate

To a mixture of a TFA salt of (S)-tert-butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylateand a TFA salt of (S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(190 mg), (S)-benzyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (Patentapplications: WO 2008/021928, WO 2008/021936 and WO 2008/021927) (213mg, 0.499 mmol), in 1,2-dimethoxyethane (10.0 mL) and water (2.0 mL) wasadded NaHCO₃ (140 mg, 1.663 mmol). The reaction mixture was degassed invacuo for 5 minutes and was flushed with nitrogen. Pd(Ph₃P)₄ (19 mg,0.017 mmol) was added and the pressure flask was capped and heated withan oil bath at 85° C. for 16 hours. The volatile component was removedin vacuo and the residue was partitioned between ethyl acetate andwater. The layers were separated and the aqueous phase was extractedseveral times with ethyl acetate. The combined organic phases were dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting material waspurified with flash chromatography (sample was dry loaded on silica geland eluted with 0-5% methanol/CH₂Cl₂) to afford partially purifiedproducts. The residue was further purified by a reverse phase HPLC(water/acetonitrile/TFA) to provide a mixture of a TFA salt of(S)-benzyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand a TFA salt of (S)-benzyl2-(5-(4-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(381 mg) which was used without further purification. LC-MS retentiontime 1.54 min; calcd. for C₄₇H₄₆N₆O₄ 758.36. found m/z 759.37 [M+H]⁺. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min and an analysis time of 4 min where Solvent A was 10%acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10%water/0.1% TFA.

Mixture of Intermediate 32 (S)-Benzyl2-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateAnd Intermediate 33 (S)-Benzyl2-(5-(4-(7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of a TFA salt of (S)-benzyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand a TFA salt of (S)-benzyl2-(5-(4-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(381 mg) and TFA (2 mL) in CH₂Cl₂ (10 mL) was stirred at ambientconditions for 4 hours. The volatile component was removed in vacuo andthe crude material was purified by a reverse phase HPLC (0 to 50%water/acetonitrile/NH₄OAc) to provide a mixture of (S)-benzyl2-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand (S)-benzyl2-(5-(4-(7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(70 mg, 21% yield) as yellow oil. LC-MS retention time 2.87 min; calcd.for C₄₂H₃₈N₆O₂ 658.31. found m/z 659.47 [M+H]⁺. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 80% Solvent A/20% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% acetonitrile/95% water/10mmol NH₄OAc and Solvent B was 95% acetonitrile/5% water/10 mmol NH₄OAc.¹H NMR (Mixture of compounds, 500 MHz, MeOD) δ ppm 8.07-8.24 (m, 4H),7.91-8.03 (m, 6H), 7.73-7.89 (m, 12H), 7.66-7.73 (m, 4H), 7.27-7.46 (m,6H), 7.09-7.18 (m, 4H), 6.97-7.04 (m, 2H), 5.01-5.21 (m, 5H), 4.83-5.01(m, 2H), 3.72-3.82 (m, 2H), 3.53-3.65 (m, 2H), 3.42-3.52 (m, 2H),3.35-3.42 (m, 4H), 2.48-2.62 (m, 2H), 2.28-2.47 (m, 4H), 2.04-2.24 (m,8H).

Intermediate 342-((S)-Pyrrolidin-2-yl)-6-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-benzo[d]imidazoletetratrifluoroacetate and Intermediate 352-((S)-Pyrrolidin-2-yl)-6-(7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-benzo[d]imidazoletetratrifluoroacetate

To a solution of a mixture of (S)-benzyl2-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand (S)-benzyl2-(5-(4-(7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(70 mg. 0.057 mmol) and potassium carbonate (K₂CO₃) in methanol (5 mL)was added a slurry of palladium on carbon (10%, 11 mg) in methanol (2mL) at ambient temperature. The reactor was vacuum purged and backfilledwith hydrogen. The reaction was stirred for 16 h under a balloon ofhydrogen. The mixture was filtered through a pad of diatomaceous earth(CELITE®) under vacuum and the filtrate was evaporated in vacuo. Thecrude material was purified by a reverse phase HPLC (0 to 50%water/acetonitrile/TFA) to provide a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-benzo[d]imidazole(50 mg) as white solid and a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-benzo[d]imidazole(24 mg) as white solid.

Analytical data for Intermediate 34: LC-MS retention time 1.06 min;calcd. for C₃₄H₃₂N₆ 524.27. found m/z 525.26 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 80% Solvent A/20% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.19 (d, J=10.4 Hz, 2H), 8.02-8.10(m, 3H), 7.84-7.96 (m, 7H), 7.77-7.83 (m, 2H), 5.14 (t, J=7.8 Hz, 1H),5.06-5.11 (m, 1H), 3.52-3.67 (m, 4H), 2.61-2.74 (m, 2H), 2.43-2.56 (m,2H), 2.30-2.42 (m, 2H), 2.18-2.30 (m, 2H).

Analytical data for Intermediate 35: LC-MS retention time 1.13 min;calcd. for C₃₄H₃₂N₆ 524.27. found m/z 525.24 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 80% Solvent A/20% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.27 (d, J=7.0 Hz, 2H), 7.99-8.06(m, 3H), 7.90-7.96 (m, 4H), 7.87 (td, J=8.2, 1.7 Hz, 2H), 7.76-7.85 (m,3H), 5.13 (t, J=7.8 Hz, 1H), 5.03-5.08 (m, 1H), 3.51-3.67 (m, 4H),2.61-2.74 (m, 2H), 2.42-2.54 (m, 2H), 2.20-2.40 (m, 4H).

(S)-tert-Butyl2-(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate

HATU (3.64 g, 9.57 mmol) was added to a stirred solution of5-bromopyridine-2,3-diamine (1.64 g, 8.70 mmol) and(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.87 g, 8.70mmol) in DMF (50 mL) and DIPEA (3.19 mL, 18.3 mmol). The reactionmixture was stirred at room temperature for 3 d, diluted with water (400mL) and extracted with EtOAc (150 mL). The organic layer was washed withbrine (50 mL), dried (MgSO₄), filtered and concentrated. The crudematerial was partially purified by flash chromatography (110 g SiO₂,1-4% MeOH/DCM) to yield 3.36 g of solidified foam. The material wasdissolved into AcOH (35.0 mL) and heated at 100° C. for 8 h. Thereaction was cooled to room temperature, concentrated and purified byflash chromatography (loaded with DCM, 80 g SiO₂, 20-40% EtOAc/Hexanes)to yield (S)-tert-butyl2-(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate (1.73g) as yellow solid. LC-MS retention time 1.33 min; m/z 365, 367 (1:1)(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (400 MHz, MeOD) δ ppm 8.40 (br s, 1H), 8.09 (br s, 1H), 5.12-4.96(m, 1H), 3.77-3.67 (m, 1H), 3.62-3.51 (m, 1H), 2.56-2.38 (m, 1H),2.15-1.90 (m, 3H), 1.46 (s, 3.5H), 1.16 (s, 5.5H).

Mixture of Intermediate 37 (S)-tert-Butyl2-(6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylateAnd Intermediate 38 (S)-tert-Butyl2-(6-bromo-1((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate

A 60% dispersion of NaH (0.120 g, 3.00 mmol) was added to a stirredsolution of (S)-tert-butyl2-(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate (1.0g, 2.7 mmol) in DMF (25 mL) and the reaction was stirred for 1.5 h atroom temperature. Then SEM-C1 (0.483 mL, 2.72 mmol) was added and thereaction was stirred 16 h. The reaction was diluted with water (˜30 mL)and EtOAc (˜35 mL), the layers were separated and the organic layer waswashed with brine (30 mL), dried (MgSO₄), filtered and concentrated. Theresidual crude yellow oil was purified by flash chromatography (80 gSiO₂, 20-30% EtOAc/hexanes) to yield a mixture of (S)-tert-butyl2-(6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylateand (S)-tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate(838 mg) as a yellow oil. The mixture was used w/o further purification.LC-MS retention time 2.54 min; m/z 497,499 (1:1) (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where Solvent A was 5%acetonitrile/95% water/10 mM ammonium acetate and Solvent B was 5%water/95% acetonitrile/10 mM ammonium acetate. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Intermediate 39 (2S,2′S)-tert-Butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-6,2-diyl))dipyrrolidine-1-carboxylateand Intermediate 40 (S)-tert-Butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate

In a microwave vial,2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (57 mg,0.150 mmol), a mixture of (5)-tert-butyl2-(6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylateand (5)-tert-butyl2-(6-bromo-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate(112 mg), cesium carbonate (147 mg, 0.450 mmol) anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (12.3 mg, 0.030mmol) were dissolved into THF (3 mL) and water (0.3 mL). An additional1.5 mL of THF was added and the reaction was sparged with bubblingnitrogen until ˜2 mL had evaporated away. To the clear solution wasadded palladium (II) acetate (3.37 mg, 0.015 mmol). The vial was flushedwith nitrogen, sealed and then heated with microwave irradiation at 120°C. for 30 min. The reaction was diluted with EtOAc (˜3 mL) and washedwith water (2 mL) and brine (2 mL). The reaction was dried (MgSO₄),filtered and concentrated to a yellow oil which was purified by flashchromatography (12 g SiO₂, 25-75% EtOAc/hexanes) to yield(2S,2′S)-tert-butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-6,2-diyl))dipyrrolidine-1-carboxylate(74 mg) as a clear colorless oil (mixture of SEM regioisomers) and(S)-tert-butyl2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate(32 mg) as a colorless oil (mixture of SEM regioisomers). Each was usedwithout further purification.

Analytical data for Intermediate 39: LC-MS retention time 3.42 min; m/z961.9 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (400 MHz, MeOD) (mixture of SEM regioisomers) δ ppm 8.84-8.75 (m,2H), 8.39-8.31 (m, 2H), 8.26-8.18 (m, 2H), 8.11 (br s, 2H), 7.92-7.84(m, 2H), 5.94-5.83 (m, 3H), 5.79 (d, J=11.0 Hz, 1H), 5.34-5.25 (m, 2H),3.86-3.57 (m, 8H), 2.61-2.39 (m, 2H), 2.34-1.99 (m, 6H), 1.45 (s, 8H),1.17 (s, 10H), 1.10-0.87 (m, 4H), −0.02 (s, 18H).

Analytical data for Intermediate 40: LC-MS retention time 3.15 min; m/z671.5 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.(mixture of SEM regioisomers) δ ppm 8.82-8.75 (m, 1H), 8.39-8.29 (m,2H), 8.21-8.15 (m, 1H), 8.07-8.01 (m, 1H), 8.11 (br s, 2H), 7.98-7.93(m, 1H), 7.89-7.80 (m, 2H), 5.94-5.85 (m, 1.5H), 5.79 (d, J=11.3 Hz,0.5H), 5.33-5.24 (m, 1H), 3.85-3.56 (m, 4H), 2.62-2.39 (m, 1H),2.33-1.99 (m, 1H), 1.49-0.87 (m, 23H), −0.02 (s, 9H).

2,6-Bis(2-((S)-pyrrolidin-2-yl)-3H-imidazo[4,5-b]pyridin-6-yl)naphthalene

4M Hydrogen chloride (2.0 mL, 8.0 mmol) in dioxane was added to astirred solution of (2S,2′S)-tert-butyl2,2′-(6,6′-(naphthalene-2,6-diyl)bis(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-6,2-diyl))dipyrrolidine-1-carboxylate(74 mg, 0.077 mmol) (mixture of SEM regioisomers) in methanol (1 mL).The reaction was stirred at room temperature for 16 h and thenconcentrated to dryness to yield a hydrochloride salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-3H-imidazo[4,5-b]pyridin-6-yl)naphthalene(51.1 mg) as yellow solid which was used without further purification.LC-MS retention time 0.83 min; m/z 501.13 (MH+). LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire 5 u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% trifluoroacetic acid and Solvent B was 10% water/90%acetonitrile/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, D₂O) δppm 8.76 (s, 2H), 8.54 (s, 2H), 8.07-7.97 (m, 4H), 7.86-7.78 (m, 2H),5.26-5.16 (m, 2H), 3.98-3.65 (m, 8H), 2.79-2.63 (m, 2H), 2.46-2.25 (m,6H).

(S)-tert-Butyl2-(6-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate

HATU (5.05 g, 13.3 mmol) was added to a stirred solution of5-bromopyrazine-2,3-diamine (2.28 g, 12.1 mmol) and(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.60 g, 12.0mmol) in DMF (50 mL) and DIPEA (4.42 mL, 25.3 mmol). The reactionmixture was stirred at room temperature for 3 d and then at 90° C. for 1d. The reaction mixture was diluted with water (350 mL) and extractedwith EtOAc (200 mL). The organic layer was washed with brine (100 mL),dried (MgSO₄), filtered and concentrated. The crude material waspartially purified by flash chromatography (110 g SiO₂, 1-4% MeOH/DCM)to yield 1.9 g of solidified foam. The material was dissolved into AcOH(35.0 mL) and heated at 95° C. for 8 h. The reaction was cooled to roomtemperature, concentrated and purified by flash chromatography (loadedwith DCM, 80 g SiO₂, 20-30% EtOAc/Hexanes) to yield (S)-tert-butyl2-(6-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate (760mg, 2.06 mmol, 17% yield) as yellow solidified foam. LC-MS retentiontime 1.28 min; m/z 366, 368 (1:1) (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 5% acetonitrile/95% water/10mM ammonium acetate and Solvent B was 5% water/95% acetonitrile/10 mMammonium acetate. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (400 MHz, MeOD) δ ppm 8.50-8.43 (m, 1H),5.11-4.99 (m, 1H), 3.77-3.68 (m, 1H), 3.62-3.51 (m, 1H), 2.57-2.40 (m,1H), 2.19-1.95 (m, 3H), 1.46 (s, 3.5H), 1.17 (s, 5.5H).

Intermediate 43 (S)-tert-Butyl2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylateand Intermediate 44 (S)-tert-Butyl2-(6-bromo-1((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate

A 60% dispersion of NaH (75 mg, 1.9 mmol) was added to a stirredsolution of (S)-tert-butyl2-(6-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate (627mg, 1.70 mmol) in DMF (15 mL) and the reaction was stirred for 1.5 h atroom temperature. Then SEM-Cl (0.30 mL, 1.7 mmol) was added and thereaction was stirred overnight. The reaction was diluted with water (˜30mL) and EtOAc (˜35 mL), the layers were separated and the organic layerwas washed with brine (30 mL), dried (MgSO₄), filtered and concentrated.The crude yellow oil was purified by flash chromatography (40 g SiO₂,20-30% EtOAc/hexanes) to yield (S)-tert-butyl2-(5-bromo-1((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate(421 mg) as a clear colorless oil and (S)-tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate(345 mg) as a clear colorless oil. The absolute regiochemistry of theSEM group was not established unambiguously, the names (and structures)may be exchanged in these intermediates.

Analytical data for Intermediate 43: LC-MS retention time 2.43 min; m/z496, 498 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (400 MHz, MeOD) δ ppm 8.52 (s, 0.5H), 8.49 (s, 0.5H), 5.90-5.72(m, 2H), 5.32-5.25 (m, 1H), 3.82-3.54 (m 4H), 2.59-2.41 (m, 1H),2.32-1.98 (m, 3H), 1.43 (s, 4.5H), 1.15 (s, 4.5H), 1.07-0.85 (m, 2H),−0.02 (s, 9H).

Analytical data for Intermediate 44: LC-MS retention time 2.41 min; m/z496, 498 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (400 MHz, MeOD) δ ppm 8.61 (s, 0.5H), 8.58 (s, 0.5H), 5.88-5.71(m, 2H), 5.28 (dd, J=8.5, 4.5 Hz, 1H), 3.82-3.54 (m 4H), 2.59-2.41 (m,1H), 2.32-1.98 (m, 3H), 1.43 (s, 4.5H), 1.15 (s, 4.5H), 1.09-0.85 (m,2H), −0.02 (s, 9H).

Intermediate 45 (2S,2′S)-tert-Butyl2,2′-(5,5′-(naphthalene-2,6-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazine-5,2-diyl))dipyrrolidine-1-carboxylateand Intermediate 46 (S)-tert-Butyl2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate

In a microwave vial,2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (149 mg,0.393 mmol), (S)-tert-butyl2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate(294 mg, 0.590 mmol) (or a SEM regioisomer), cesium carbonate (384 mg,1.18 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (32.3mg, 0.079 mmol) were dissolved into THF (4 mL) and water (0.4 mL). Anadditional 1.5 mL of THF was added and the reaction was sparged withbubbling nitrogen until the 1.5 mL had evaporated away. To the clearsolution was added palladium(II) acetate (8.83 mg, 0.039 mmol). The vialwas flushed with nitrogen, sealed and then heated with microwaveirradiation at 120° C. for 30 min. The reaction was diluted with EtOAc(˜3 mL) and washed with water (2 mL) and brine (2 mL). The reaction wasdried (MgSO₄), filtered and concentrated to a yellow oil which waspurified by flash chromatography (12 g SiO₂, 25-75% EtOAc/hexanes) toyield (2S,2′S)-tert-butyl2,2′-(5,5′-(naphthalene-2,6-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazine-5,2-diyl))dipyrrolidine-1-carboxylate(or a SEM regioisomer) (210 mg) as a yellow solidified foam and(S)-tert-butyl2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate(or a SEM regioisomer) (53.5 mg) as a colorless oil.

Analytical date for Intermediate 45: LC-MS retention time 3.27 min; m/z963.89 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (400 MHz, MeOD) (mixture of SEM regioisomers) δ ppm 9.29-9.15 (m2H), 8.79-8.66 (m, 2H), 8.43-8.29 (m, 2H), 8.20-7.98 (m, 2H), 6.03-5.84(m, 4H), 5.34 (dd, J=8.3, 4.3 Hz, 2H), 3.87-3.70 (m, 6H), 3.68-3.58 (m,2H), 2.63-2.43 (m, 2H), 2.36-1.14 (m, 4H), 2.14-1.99 (m, 2H), 1.46 (s,8H), 1.17 (s, 10H), 1.35-0.85 (m, 4H), −0.02 (s, 18H).

Analytical date for Intermediate 45: LC-MS retention time 3.07 min; m/z672.52 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.

2,6-Bis(2-((S)-pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)naphthalene

4M Hydrogen chloride (6.0 mL, 24 mmol) in dioxane was added to a stirredsolution of (2S,2′S)-tert-butyl2,2′-(5,5′-(naphthalene-2,6-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazine-5,2-diyl))dipyrrolidine-1-carboxylate(210 mg, 0.218 mmol) (absolute regiochemistry of the SEM was notestablished) in methanol (3 mL). The reaction was stirred at roomtemperature for 16 h and concentrated to dryness to yield ahydrochloride salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)naphthalene(143 mg) as orange solid which was used without further purification.LC-MS retention time 0.90 min; m/z 503.21 (MH+). LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire 5 u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% trifluoroacetic acid and Solvent B was 10% water/90%acetonitrile/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, D₂O) δppm 8.59 (s, 2H), 7.94 (s, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.76 (d, J=8.5Hz, 2H), 5.23-5.16 (m, 2H), 3.98-3.66 (m, 8H), 2.78-2.64 (m, 2H),2.47-2.28 (m, 6H).

tert-Butyl(2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate

To a solution of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(885 mg, 1.78 mmol), DMAP (10.8 mg, 0.089 mmol) and triethylamine (1.2mL, 8.9 mmol) in DMF (30 mL) at room temp was added in one portiondi-tert-butyl dicarbonate (387 mg, 1.78 mmol). The reaction mixture wasstirred overnight at room temperature and purified on a BIOTAGE® (dryloaded to a 80 g silica gel cartridge and eluted with a gradient of 0 to50% DCM in MeOH), to yield tert-butyl(2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate(500 mg, 0.835 mmol, 47.1% yield) as orange solid. LC-MS retention time1.207 min; m/z 599.25 [M+H]⁺. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Sunfire 5 u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 3 min, a hold time of 1 min and an analysis time of 4min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and SolventB was 90% acetonitrile/10% water/0.1% TFA. MS data was determined usinga MICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz,MeOD) δ ppm 8.27 (d, J=3.1 Hz, 1H), 8.23 (s, 1H), 8.04-8.17 (m, 4H),8.03 (s, 1H), 7.88-7.97 (m, 3H), 7.75-7.83 (m, 2H), 5.28-5.35 (m, 1H),5.11 (t, J=7.8 Hz, 1H), 3.75-3.83 (m, 1H), 3.60-3.72 (m, 2H), 3.51-3.59(m, 1H), 2.60-2.74 (m, 2H), 2.40-2.50 (m, 1H), 2.21-2.38 (m, 3H),2.10-2.20 (m, 2H), 1.52 (s, 4H), 1.25 (s, 4H).

tert-Butyl(2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate

To a solution of tert-butyl(2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate(400 mg, 0.668 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(176 mg, 1.00 mmol) and DIEA (0.583 mL, 3.34 mmol) in DMF (10 mL) wasadded HATU (381 mg, 1.00 mmol). The reaction mixture was stirred 2 h atroom temperature and then purified by prep HPLC (using a Waters SunfireC18 column 30×150 mm 5 u eluted with a gradient of 0 to 50%ACN-Water+0.1% TFA) to yield a TFA salt of tert-butyl(2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate(445 mg) as yellow solid. LC-MS retention time 1.317 min; m/z 756.28[M+H]⁺. LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min,a hold time of 1 min and an analysis time of 4 min where Solvent A was10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-methyl-1-(((2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

To a solution of a TFA salt of tert-butyl(2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate(445 mg) in DCM (10 mL) at room temp was added TFA (1 mL, 13 mmol). Themixture was stirred at rt for 3 h, concentrated, and the residue wasdiluted in MeOH, loaded onto a Strata XC MCX cartridge and washed withmethanol. The compound was release from the cartridge by eluting with asolution of 2M ammonia in methanol and then evaporated under reducedpressure to give methyl((1S)-2-methyl-1-(((2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate(275 mg) as orange solid LC-MS retention time 1.120 min; m/z 656.27[M+H]⁺. LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min,a hold time of 1 min and an analysis time of 4 min where Solvent A was10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD)δ ppm 8.26 (br s, 1H), 8.22 (br s, 1H), 8.08-8.16 (m, 3H), 8.04-8.08 (m,1H), 8.03 (s, 1H), 7.86-7.96 (m, 3H), 7.73-7.82 (m, 2H), 5.88-5.93 (m,0.1H), 5.37-5.44 (m, 0.9H), 5.07-5.15 (m, 1H), 4.28-4.33 (m, 1H),4.12-4.19 (m, 0.8H), 4.06-4.10 (m, 0.2H), 3.94-4.02 (m, 1H), 3.59-3.75(m, 4H), 3.50-3.59 (m, 1H), 2.63-2.74 (m, 2H), 2.41-2.47 (m, 1H),2.23-2.40 (m, 5H), 2.06-2.16 (m, 1H), 1.00-1.04 (m, 0.4H), 0.94-1.00 (m,3H), 0.88-0.93 (m, 2.6H).

Intermediate 51 (S)-tert-Butyl2-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand Intermediate 52 (2S,2′S)-tert-Butyl2,2′-(4,4′-(naphthalene-2,6-diyl)bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate

A 100 mL pressure vessel equipped with a magnetic stir bar was chargedwith 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene(2.00 g, 5.26 mmol), (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.10 g, 5.79 mmol)and Pd(Ph₃P)₄ (0.058 g, 0.05 mmol) in DME (47.8 mL) and water (4.8 mL).The solution was degassed under vacuum for 5 min and the reactor wasback filled with nitrogen. The vessel was sealed and the reactionmixture was heated overnight at 120° C. The reaction was cooled to roomtemperature and the volatiles were removed under. The residue waspartitioned between water and EtOAc and the water layer was extractedwith additional EtOAc. The combined organic layers were dried (Na₂SO₄),filtered, and concentrated. The crude product was purified with aBIOTAGE® (dry loaded onto a 90 g silica gel cartridge and eluted with agradient of 0 to 30% EtOAc in DCM) and repurified with a BIOTAGE® (dryloaded onto a 80 g silica gel cartridge and eluted with a gradient of 0to 50% EtOAc in DCM) to yield (S)-tert-butyl2-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(949 mg) as a yellow solid. The material (contaminated with(2S,2′S)-tert-butyl2,2′-(4,4′-(naphthalene-2,6-diyl)bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate)was used in the next step without further purification. LC-MS retentiontime 1.760 min; m/z 490.21 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters Sunfire 5 u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode.

The preparative HPLC from the next reaction yielded (2S,2′S)-tert-butyl2,2′-(4,4′-(naphthalene-2,6-diyl)bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate(92 mg, 0.111 mmol, 11% yield) as yellow solid LC-MS retention time1.113 min; m/z 599.24 [M+H]⁺. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Sunfire 5 u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 3 min, a hold time of 1 min and an analysis time of 4min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and SolventB was 90% acetonitrile/10% water/0.1% TFA. MS data was determined usinga MICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz,MeOD) δ ppm 8.35 (br s, 2H), 8.13 (br s, 2H), 8.08 (br s, 1H), 8.00 (brs, 1H), 7.95 (m, 2H), 5.18 (br s, 2H), 3.68-3.78 (m, 2H), 3.62 (br s,2H), 2.51-2.68 (m, 2H), 2.21 (br s, 2H), 2.06-2.15 (m, 4H), 1.50 (br s,9H), 1.31 (br s, 9H).

(S)-tert-Butyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A 100 mL pressure vessel equipped with a magnetic stir bar was chargedwith (S)-tert-butyl2-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(500 mg, 1.02 mmol), (S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (601 mg,1.53 mmol) and Pd(Ph₃P)₄ (58 mg, 0.05 mmol) in DME (10 mL) and water(1.0 mL). The solution was degassed under vacuum for 5 min and thereactor was back filled with nitrogen. The mixture was heated for 8 h at120° C., additional Pd(Ph₃P)₄ (57.8 mg, 0.05 mmol) was added and themixture was degassed and stirred overnight at 130° C. The reaction wascooled to room temperature and the volatiles were removed under vacuum.The residue was partitioned between water and EtOAc and the water layerwas extracted with additional EtOAc. The combined organic layers weredried (Na₂SO₄), filtered, and concentrated. The crude product waspurified on a BIOTAGE® (dry loaded onto a 90 g silica gel cartridge andeluted with a gradient of 5 to 100% EtOAc in DCM) and then repurified byprep HPLC (using a Waters Sunfire C18 column 30×100 mm 5 u elutedMeOH-Water+0.1% TFA) to yield a TFA salt of (S)-tert-butyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(50 mg). LC-MS retention time 1.278 min; m/z 675.70 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (500 MHz, MeOD) δ ppm 8.31 (d, J=15.9 Hz, 2H), 8.14-8.18(m, 1H), 8.10 (d, J=8.85 Hz, 1H), 8.05 (s, 0.6H), 7.96-8.03 (m, 4H),7.85-7.94 (m, 3.4H), 5.11-5.23 (m, 2H), 3.69-3.77 (m, 2H), 3.62 (br s,2H), 2.51-2.67 (m, 2H), 2.16-2.26 (m, 2H), 2.05-2.16 (m, 4H), 1.51 (s,9H), 1.32 (s, 9H).

2-((2S)-2-Pyrrolidinyl)-4-(4-(6-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole

To a solution of a TFA salt of (S)-tert-butyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(50 mg) in DCM (10 mL) was added TFA (2.0 mL, 26 mmol) in one portion.The mixture was agitated at room temperature for 2 h. The reaction wasconcentrated under vacuum to yield a TFA salt of2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole(51.5 mg) as orange solid, which was used without further purification.LC-MS retention time 0.978 min; m/z 475.19 [M+H]⁺. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a WatersSunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. HPLC-MS (TFA) 78457-087 using a Waters Sunfire C18 column 4.6×50mm 5 u showed the reaction was complete peak found at RT=0.978 min.MH+=475.19. ¹H NMR (500 MHz, MeOD) δ ppm 8.34 (s, 1H), 8.20 (s, 1H),8.03 (dd, J=14.2, 8.7 Hz, 2H), 7.84-7.96 (m, 7H), 7.79-7.84 (m, 1H),4.99-5.11 (m, 2H), 3.48-3.63 (m, 4H), 2.57-2.70 (m, 2H), 2.41-2.55 (m,2H), 2.29-2.41 (m, 2H), 2.15-2.29 (m, 2H).

4,4′-(2,6-Naphthalenediyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole)

To a solution of a TFA salt of (2S,2′S)-tert-butyl2,2′-(4,4′-(naphthalene-2,6-diyl)bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate(82 mg) in DCM (2 mL) at room temperature was added TFA (2.0 mL, 26mmol) in one portion. The mixture was stirred for 3 h at roomtemperature, purified by prep HPLC (Waters Sunfire C18 column 30×100 mm5 u eluted with a gradient of 5 to 90% MeOH-Water+0.1% TFA) andrepurified by prep HPLC (PHENOMENEX® Luna C18 column 30×100 mm 10 ueluted with a gradient of 10 to 90% methanol-Water+0.1% TFA) to yield aTFA salt of4,4′-(2,6-naphthalenediyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole) (68mg) as tan solid. LC-MS retention time 0.978 min; m/z 399.18 [M+H]⁺. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min and an analysis time of 4 min where Solvent A was 10%acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.31 (s, 2H),7.95-8.00 (m, 2H), 7.91-7.95 (m, 2H), 7.85 (s, 2H), 5.03 (t, J=8.2 Hz,2H), 3.49-3.62 (m, 4H), 2.59-2.67 (m, 2H), 2.42-2.52 (m, 2H), 2.31-2.40(m, 2H), 2.17-2.28 (m, 2H).

(S)-tert-Butyl2-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-Butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (750mg, 2.07 mmol) and copper(I) iodide (79 mg, 0.41 mmol) were dissolvedinto DMF (20 mL) and triethylamine (1.439 mL, 10.33 mmol). The reactionsolution was vacuum flushed for 10 minutes (aspirator vacuum, flushedwith nitrogen) and then ethynyltrimethylsilane (1.2 mL, 8.3 mmol) andfinally Pd(PPh₃)₄ (119 mg, 0.103 mmol) were added. The flask was flushedwith nitrogen, seal and heated at 50° C. overnight. The reaction wasconcentrated to a crude black tar, dissolved into DCM and purified viaBIOTAGE® Horizon (80 g SiO₂, 20-40% EtOAc/hexanes) to yield(S)-tert-butyl2-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(546 mg, 1.64 mmol, 79% yield) as a yellow solid. This material was usedwithout further purification. LC-MS retention time 1.393 min; m/z 332.33(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and SolventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.19-7.13 (m, 1H), 4.92-4.85 (m, 1H),3.43-3.31 (m, 2H), 3.04-2.83 (m, 1H), 2.20-1.88 (m, 3H), 1.51 (s, 3H),1.49 (s, 6H), 0.25 (s, 3H), 0.23 (s, 6H).

(S)-tert-Butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-Butyl2-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(537 mg, 1.61 mmol) was dissolved into MeOH (20 mL) and then potassiumcarbonate (22 mg, 0.16 mmol) was added and the reaction was stirred atrt for 3 h. The reaction was concentrated, dissolved intodichcloromethane, loaded onto a SiO₂ column and purified by BIOTAGE®Horizon (30-50% EtOAc/hexanes) to yield (S)-tert-butyl2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (346 mg, 1.32mmol, 82% yield) as an off-white solid. LC-MS retention time 0.878 min;m/z 260.35 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and SolventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.21-7.17 (m, 1H), 4.92-4.87 (m, 1H),3.43-3.30 (m, 2H), 3.05 (s, 1H), 3.03-2.85 (m, 1H), 2.20-1.88 (m, 3H),1.60-1.45 (m, 9H).

tert-Butyl(2S)-2-(4-((6-((2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)ethynyl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

(S)-tert-Butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(340 mg, 1.30 mmol), 2,6-dibromonaphthalene (744 mg, 2.60 mmol) andcopper(I) iodide (12.39 mg, 0.065 mmol) were slurried into DMF (10 mL)and triethylamine (0.54 mL, 3.9 mmol). The solution was vacuum flushedwith nitrogen (5×), treated with Pd(PPh₃)₄ (75 mg, 0.065 mmol) and thenvacuum flushed with nitrogen (2×). The cloudy yellow solution wasstirred under nitrogen at rt for 3 h. The reaction was concentrated to ayellow-orange semi-solid, slurried into DMF/MeOH (˜1:1), filtered andpurified in five injections by prep HPLC (acetonitrile/water with 10 mMammonium acetate, 15-100%). The fractions containing the desired productwere combined and concentrated to yield tert-butyl(2S)-2-(4-((6-((2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)ethynyl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate(70 mg, 0.11 mmol, 18% yield) as a light yellow solid. LC-MS retentiontime 1.448 min; m/z 647.45 (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10 u C183.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where Solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.70 (br s, 2H),7.98 (s, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.30-7.25(m, 2H, under solvent peak), 4.95 (dd, J=7.3, 3.3 Hz, 2H), 3.46-3.37 (m,4H), 3.08-2.91 (m, 2H), 2.24-2.08 (m, 4H), 2.03-1.92 (m, 2H), 1.51 (s,18H).

4,4′-(2,6-Naphthalenediyldi-2,1-ethynediyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole)

(2S,2′S)-tert-Butyl2,2′-(5,5′-(naphthalene-2,6-diylbis(ethyne-2,1-diyl))bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(32 mg, 0.049 mmol) was dissolved into dichloroethane (2 mL) and thenTFA (1 mL, 13 mmol) was added. The solution was stirred at rt for 1 h.The reaction was concentrated to dryness to yield a TFA salt of4,4′-(2,6-naphthalenediyldi-2,1-ethynediyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole)(41.6 mg) as tan solid. ¹H NMR (500 MHz, CD₃OD) δ ppm 8.05 (s, 2H), 7.89(d, J=8.3 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.52 (s, 2H), 4.89-4.84 (m,2H), 3.56-3.44 (m, 4H), 2.59-2.50 (m, 2H), 2.42-2.24 (m, 4H), 2.26-2.14(m, 2H).

(1R,5R)-tert-Butyl3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Hunig's Base (7.69 mL, 44.0 mmol) was added to a stirred solution of2-bromo-1-(4-bromophenyl)ethanone (12.23 g, 44.0 mmol) and(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (10 g, 44 mmol) in dry MeCN (400 mL). The mixture was stirred for16 h at RT. The solvent was removed in vacuo and the residue was takenup in ethyl acetate and washed with saturated sodium bicarbonatesolution and brine, dried (sodium sulfate), filtered and concentrated.In a pressure vessel the residue was taken up in xylene (400 mL) andammonium acetate (33.9 g, 440 mmol) was added. The vessel was sealed andheated at 140° C. for 2 h. The solvent was removed in vacuo and theresidue was taken up in ethyl acetate and washed with saturated sodiumbicarbonate solution (pH=9), brine, dried over sodium sulfate andconcentrated. The crude product, as a reddish orange foam, was dissolvedin methylene chloride and placed onto a 300 g Thompson silica gelcartridge (eluted with 20% B to 100% B for 4000 mL where Solvent B=ethylacetate and Solvent A=hexanes) to yield (1R,3S,5R)-tert-butyl3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(16.67 g, 39.1 mmol, 88.8% yield) as a golden-brown foam. LC-MSretention time 1.762 min; m/z 403.94 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® LunaS10 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 7.62 (br d, J=8.6 Hz, 2H), 7.50 (br d, J=8.6Hz, 2H), 7.37 (s, 1H), 4.66 (br s, 1H), 3.58 (br s, 1H), 2.56-2.47 (m,1H), 2.36-2.27 (m, 1H), 1.75-1.67 (m, 1H), 0.97 (br s, 9H), 0.88-0.81(m, 1H), 0.64-0.57 (m, 1H).

(1R,3S,5R)-tert-Butyl3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a solution of(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (9.85 g, 43.3 mmol) in THF (200 mL) at 0° C. was added dropwiseborane-methyl sulfide complex (282 mL, 563 mmol) over 30 min. The icebath was removed, the mixture was stirred for 1 h and then heated atreflux for 2 h. The mixture was cooled to 0° C., slowly quenched withmethanol (˜200 mL) and concentrated under vacuum. The residue wasdissolved in DCM and washed with water (emulsion), 1N HCl, sat NaHCO₃aq, and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated to yield (1R,3S,5R)-tert-butyl3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (8.43 g, 39.5mmol, 91% yield) as colorless oil. LC-MS retention time 1.398 min; m/z236.20 [M+Na]⁺. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min and an analysis time of 4 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90%methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm3.72-3.79 (m, 1H), 3.52-3.64 (m, 3H), 3.15-3.24 (m, 1H), 2.00-2.08 (m,1H), 1.62-1.72 (m, 1H), 1.54-1.62 (m, 1H), 1.45-1.51 (m, 9H), 0.84 (brs, 1H), 0.36 (td, J=5.0, 2.4 Hz, 1H).

(1R,3S,5R)-tert-Butyl 3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a solution of (1R,3S,5R)-tert-butyl3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (4.85 g, 22.74mmol) in DCM (125 mL) at 0° C. was added Dess-Martin periodinane (11.57g, 27.3 mmol). The reaction was warmed up to RT and stirred for 3 h. Thereaction was poured into a saturated aq solution of NaHCO₃ then ca ˜20 gof Na₂S₂O₃ was added and stirred for 1 h. The layers were separated andthe aqueous layer was extracted several times with DCM. The combinedorganic extracts were dried over Na₂SO₄ and evaporated in vacuo. Theresidue was purified by flash column chromatography (BIOTAGE®), elutingwith a gradient of 0 to 40% EtOAc/hexanes to afford(1R,3S,5R)-tert-butyl 3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(4.47 g, 21.2 mmol, 93% yield) as colorless oil. LC-MS retention time0.813 min; m/z no ionization (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters Sunfire 5 u C184.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where Solvent A was 10% MeOH/90% H₂O/0.1% TFA andSolvent B was 10% H₂O/90% MeOH/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 9.48 (br s, 1H), 3.67-3.97 (m, 1H), 3.33-3.59 (m,1H), 2.10-2.31 (m, 2H), 1.56-1.67 (m, 1H), 1.47 (br s, 9H), 0.80 (br s,1H), 0.55 (br s, 1H).

(1R,3S,5R)-tert-Butyl3-(1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Ammonium hydroxide (16.40 mL, 421 mmol) was added dropwise to a stirredsolution of (1R,3S,5R)-tert-butyl3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (4.4 g) in methanol (15mL) at 0° C. The reaction was allowed to warm to room temp and stirredfor 45 min. Then, oxalaldehyde 40% H₂O (5.32 mL, 46.3 mmol) was addeddropwise and the reaction mixture was stirred overnight. The reactioncolor turned brown over time. The reaction was diluted with brine andconcentrated to remove the volatile solvent. The remaining aqueous layerwas then extracted several times with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄ evaporated under vacuum. Theresidue was purified by flash column chromatography (BIOTAGE®), elutingwith a gradient of 0 to 70% EtOAc/hexanes to afford(1R,3S,5R)-tert-butyl3-(1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.71 g,14.9 mmol, 71% yield) as white solid. LC-MS retention time 0.772 min;m/z 250.20 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (400 MHz, chloroform-d) δ ppm 10.43 (br s,1H), 6.99 (s, 2H), 4.86 (dd, J=9.0, 5.0 Hz, 1H), 3.35 (br s, 1H), 3.20(br s, 1H), 2.28-2.38 (m, 1H), 1.71-1.80 (m, 1H), 1.49 (s, 9H),0.83-0.90 (m, 1H), 0.45 (br s, 1H).

(1R,3S,5R)-tert-Butyl3-(4,5-diiodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Iodine (I₂, 12.43 g, 49.0 mmol) was added to a solution of3-(1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (5.55 g,22.3 mmol) and sodium carbonate (7.08 g, 66.8 mmol) in dioxane (56 mL)and water (56 mL) and the reaction mixture was stirred in the dark for16 h at room temperature. The reaction mixture was diluted with EtOAcand washed an aqueous saturated solution of sodium thiosulfate. Thelayers were separated and the aqueous layer was extracted with EtOAc.The combined organic layers were dried over Na₂SO₄ and evaporated undervacuum. The residue was purified by flash column chromatography(BIOTAGE®), eluting with a gradient of 0 to 100% EtOAc/hexanes to afford(1R,3S,5R)-tert-butyl3-(4,5-diiodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(8.3 g, 16 mmol, 71% yield) as white solid. LC-MS retention time 1.455min; m/z 502.07 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (400 MHz, MeOD) δ ppm 4.51 (br s, 1H), 3.56(br s, 1H), 2.40-2.54 (m, 1H), 2.18-2.27 (m, 1H), 1.65-1.73 (m, 1H),1.20-1.40 (br s, 9H), 0.82 (dt, J=8.6, 5.8 Hz, 1H), 0.58 (br s, 1H).

(1R,3S,5R)-tert-Butyl3-(4-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A 250 mL pressure flask equipped with a stir bar was charge with asolution of (1R,3S,5R)-tert-butyl3-(4,5-diiodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(8.3 g, 17 mmol) in EtOH (83 mL) and water (83 mL). Then, sodium sulfite(20.88 g, 166 mmol) was added and the mixture was heated at 90° C. for16 h. The reaction mixture was extracted with EtOAc and the combinedorganic layers were dried over Na₂SO₄ and evaporated under vacuum. Theresidue was purified by flash column chromatography (BIOTAGE®), elutingwith a gradient of 0 to 15% EtOAc/DCM to afford (1R,3S,5R)-tert-butyl3-(4-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(3.84 g, 10.2 mmol, 62% yield) as yellow solid along with the fullyreduced product (1R,3S,5R)-tert-butyl3-(1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (550 mg,2.21 mmol, 13% yield). LC-MS retention time 0.932 min; m/z 376.22 (MH+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 7.12 (br s, 1H), 4.59(br s, 1H), 3.44-3.64 (br s, 1H), 2.40-2.52 (m, 1H), 2.17-2.30 (m, 1H),1.65-1.73 (m, 1H), 1.27 (br s, 9H), 0.84 (dt, J=8.5, 5.7 Hz, 1H), 0.58(br s, 1H).

(1R,3S,5R)-tert-Butyl3-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylateand Intermediate 67 (1R,1′R,3S,3′S,5R,5′R)-tert-Butyl3,3′-(5,5′-(4,4′-(naphthalene-2,6-diyl)bis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[3.1.0]hexane-2-carboxylate)

A solution of2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (1.0 g,2.6 mmol), (1R,3S,5R)-tert-butyl3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.06 g, 2.63 mmol), Na₂CO₃ (0.837 g, 7.89 mmol) in DME (20 mL) andwater (2 mL) was degassed under vacuum for 10 min. The mixture washeated at 80° C. and then Pd(Ph₃P)₄ (0.152 g, 0.132 mmol) was addedunder a stream of nitrogen. The reactor was sealed and the heating waspursued further at 120° C. for 16 h. The DME was removed in vacuo andthe crude material was partitioned between EtOAc/H₂O. The layers wereseparated and the aqueous layer was extracted several times with EtOAc.The combined organic extracts were dried over Na₂SO₄ and evaporated invacuo. The residue was purified by flash column chromatography(BIOTAGE®), eluting with a gradient of 0 to 5% MeOH/DCM to afford thepartially pure target product contaminated with reaction side products.The impure product was purified again by flash column chromatography(BIOTAGE®), eluting with a gradient of 50 to 100% EtOAc/hexanes, thenthe column was flushed with 10% MeOH/DCM to afford (1R,3S,5R)-tert-butyl3-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(606 mg) as yellow foam. LC-MS retention time 1.608 min; m/z 578.4(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, chloroform-d, Partial NMR) δ ppm4.89 (br s, 1H), 3.20-3.66 (m, 1H), 2.33-2.50 (m, 1H), 1.76-1.86 (m,1H), 1.52 (br s, 9H), 1.24-1.32 (m, 12H), 0.87-0.93 (m, 1H), 0.51 (br s,1H).

(1R,3S,5R)-tert-Butyl3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A solution of (1R,3S,5R)-tert-butyl3-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(568 mg), (1R,3S,5R)-tert-butyl3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (369mg, 0.983 mmol), Na₂CO₃ (313 mg, 2.95 mmol) in DME (10 mL) and water (2mL) was degassed under vacuum for 10 min. The mixture was heated at 80°C. and then Pd(Ph₃P)₄ (114 mg, 0.098 mmol) was added under a stream ofnitrogen. The reactor was sealed and the heating was pursued further at130° C. overnight. The DME was removed in vacuo and the crude materialwas partitioned between EtOAc/H₂O. The layers were separated and theaqueous layer was extracted several times with EtOAc. The combinedorganic extracts were dried over Na₂SO₄ and evaporated in vacuo. Theresidue was purified by flash column chromatography (BIOTAGE®), elutingwith a gradient of 20 to 100% EtOAc/hexanes, then 5% MeOH/DCM to affordthe partially pure (1R,3S,5R)-tert-butyl3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(277 mg). LC-MS retention time 1.578 min; m/z 699.56 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where Solvent A was 10% MeOH/90%H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 7.62-7.69 (m, 6H), 7.53-7.59 (m, 4H), 6.95 (s,2H), 4.67 (br s, 2H), 3.46-3.56 (m, 2H), 2.50-2.59 (m, 0.5H), 2.32-2.49(m, 2H), 2.27 (br s, 1.5H), 1.65-1.78 (m, 2H), 1.28 (br. s, 18H),0.80-0.88 (m, 2H), 0.53-0.66 (m, 2H).

(1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

To a solution of (1R,3S,5R)-tert-butyl3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(275 mg) in DCM (10 mL) was added TFA (2 mL, 26.0 mmol). The mixture wasstirred for 2 h at room temperature. The volatiles were removed undervacuum and the crude residue was purified by a reverse phase HPLC(water/MeOH/TFA) to afford a TFA salt of(1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(106 mg) as tan solid. LC-MS retention time 1.153 min; m/z 499.36 (MH+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.33 (s, 1H), 8.19 (s,1H), 7.99-8.05 (m, 2H), 7.85-7.95 (m, 6H), 7.83 (s, 1H), 7.76 (s, 1H),4.78 (q, J=9.4 Hz, 2H), 3.47-3.54 (m, 2H), 2.65-2.74 (m, 4H), 2.02-2.12(m, 2H), 1.18-1.25 (m, 2H), 0.97-1.05 (m, 2H).

tert-Butyl(1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinolinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a degassed solution of 6-bromo-2-chloroquinoline (30 mg, 0.12 mmol),Na₂CO₃ (39.3 mg, 0.371 mmol) and (1R,3S,5R)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(116 mg, 0.272 mmol) in dioxane (1 mL) and H₂O (0.2 mL) was addedPd(Ph₃P)₄ (14.3 mg, 0.012 mmol) and the mixture was stirred at 110° C.for 2 h. The reaction mixture was diluted with MeOH, and purified byprep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield a TFA salt oftert-butyl(1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinolinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(60.6 mg, 0.057 mmol, 46.3% yield) as a yellow solid. LC-MS retentiontime 2.05 min; m/z 724 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10.Solvent A=90% water:10% methanol: 0.1% TFA. Solvent B=10% water:90%methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100.Gradient Time=3 min. Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.68(1H, d, J=8.5 Hz), 8.60 (1H, s), 8.44 (1H, dd, J=8.5, 1.5 Hz), 8.39 (1H,d, J=1.3 Hz), 8.33 (1H, d, J=8.8 Hz), 8.23-8.29 (1H, m), 8.25 (1H, d,J=8.5 Hz), 8.19 (1H, s), 8.08 (1H, d, J=9.0 Hz), 7.96 (1H, d, J=9.0 Hz),7.93 (1H, d, J=9.5 Hz), 5.02-5.12 (2H, m), 3.70 (2H, br s), 2.74-2.85(2H, m), 2.45-2.57 (2H, m), 1.84-1.96 (2H, m), 1.05-1.68 (18H, m),0.89-1.01 (2H, m), 0.77-0.86 (2H, m).

2,6-Bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoline

A TFA salt of tert-butyl(1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinolinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(51 mg, 0.054 mmol) was mixed with a dioxane solution of HCl (0.5 mL,2.00 mmol), and stirred at rt for 2 h. The volatiles were removed toyield an HCl salt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoline(53 mg) as yellow solid. LC-MS retention time 1.20 min; m/z 524 [M+H]⁺.(Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220).

tert-Butyl(1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinoxalinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Pd(Ph₃P)₄ (14.24 mg, 0.012 mmol) was added to a degassed solution of6-bromo-2-chloroquinoxaline (30 mg, 0.123 mmol), NaHCO₃ (31.1 mg, 0.370mmol) and (1R,3S,5R)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(131 mg, 0.308 mmol) in dioxane (1.0 mL) and H₂O (0.2 mL) and themixture was stirred at 100° C. for 2 h, then at 110° C. for 2 h. Thereaction was diluted with MeOH, filtered and the filtrate was purifiedby prep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield a TFA salt oftert-butyl(1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinoxalinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(67.6 mg) as a yellow solid. LC-MS retention time 2.13 min; m/z 725[M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 9.60 (1H, s), 8.71 (1H,s), 8.56 (1H, dd, J=8.8, 1.5 Hz), 8.45 (1H, d, J=1.5 Hz), 8.26-8.35 (2H,m), 8.21 (1H, s), 8.06-8.11 (1H, m), 7.91-7.99 (2H, m), 5.02-5.13 (2H,m), 3.70 (2H, br s), 2.79 (2H, dd, J=13.4, 9.2 Hz), 2.43-2.57 (2H, m),1.83-1.96 (2H, m), 1.07-1.65 (18H, m), 0.95 (2H, m), 0.77-0.85 (2H, m).

2,6-Bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxaline

TFA (0.25 mL, 3.24 mmol) was added to a solution of a TFA salt oftert-butyl(1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinoxalinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(65 mg) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. Thevolatiles were removed and the residue was triturated with Et₂O. Theresulting solid was collected via filtration funnel and rinsed with Et₂Oto yield a TFA salt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxaline(60 mg) as yellow solid. LC-MS retention time 1.51 min; m/z 525 [M+H]⁺.(Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 9.52 (1H, s), 8.58 (1H,s), 8.36 (1H, s), 8.22-8.33 (2H, m), 8.30 (1H, d, J=9.5 Hz), 8.08 (1H,s), 7.76-7.94 (2H, m), 7.83 (1H, d, J=9.5 Hz), 4.80-5.05 (2H, m),3.45-3.61 (2H, m), 2.70-2.92 (2H, m), 2.50-2.67 (2H, m), 2.00-2.18 (2H,m), 1.26 (2H, br s), 1.04 (2H, br s).

(S)-tert-Butyl2-(5-(4-bromophenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

NCS (0.51 g, 3.82 mmol) was added to a solution of tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g,2.55 mmol) in DMF (25 mL) and the mixture was heated at 50° C.overnight. The volatiles were removed under vacuum. The residue waspurified by flash column chromatography (BIOTAGE®), eluting with agradient of 0 to 10% EtOAc/DCM to afford the partially pure(S)-tert-butyl2-(5-(4-bromophenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.04 g) as yellow foam. LC-MS retention time 1.99 min; m/z 427.12(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 7.63 (s, 4H), 4.74-4.81(m, 1H), 3.64-3.72 (m, 1H), 3.45-3.55 (m, 1H), 2.27-2.42 (m, 1H),2.00-2.15 (m, 2H), 1.90-2.00 (m, 1H), 1.48 (m, 3H), 1.27 (m, 6H).

(S)-tert-Butyl2-(4-chloro-5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A solution of (5)-tert-butyl2-(5-(4-bromophenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.04 g, 2.44 mmol) and2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (0.926g, 2.44 mmol) in DME (10 mL) and water (2 mL) was degassed under vacuumfor 10 min. The mixture was heated at ca ˜80° C., Pd(Ph₃P)₄ (0.282 g,0.244 mmol) was added under a stream of nitrogen and the reactor wassealed. The heating was pursued further to 130° C. for 8 h. AdditionalPd(PPh₃)₄ (100 mg) was added and the heating was pursued overnight. TheDME was removed in vacuo and the crude material was partitioned betweenEtOAc/H₂O. The layers were separated and the aqueous layer was extractedseveral times with EtOAc. The combined organic extracts were dried overNa₂SO₄ and evaporated in vacuo. The residue was purified by flash columnchromatography (BIOTAGE®), eluting with a gradient of 0 to 100%EtOAc/hexanes to afford the partially pure (S)-tert-butyl2-(4-chloro-5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatecontaminated with triphenylphosphine (292 mg). A small aliquot waspurified further by a reverse phase HPLC (water/acetonitrile/TFA) toafford the pure title material. The remaining material was used insubsequent step without further purification. LC-MS retention time 2.227min; m/z 598.46 (MH−) LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/10 mM ammonium acetate and Solvent B was10% H₂O/90% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD,TFA salt, partial NMR) δ ppm 3.71 (br s, 2H), 3.55 (br s, 2H), 2.45 (brs, 1H), 2.07-2.17 (m, 2H), 1.97-2.06 (m, 1H), 1.50 (s, 3H), 1.43 (m,6H), 1.31 (br s, 6H).

(S)-tert-Butyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A solution of (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (163 mg, 0.450mmol), (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (163 mg, 0.450mmol), sodium bicarbonate (113 mg, 1.350 mmol) in a solvent mixture ofDME (10 mL) and water (2 mL) was degassed under vacuum for 10 min. Themixture was heated at 80° C. then Pd(Ph₃P)₄ (52.0 mg, 0.045 mmol) wasadded and the reactor was flushed with nitrogen and sealed. The heatingwas pursued further to 120° C. for 16 h. The flask was cooled to roomtemperature, the DME was removed in vacuo and the crude material waspartitioned between DCM/H₂O. The layers were separated and the aqueouslayer was extracted several times with DCM. The combined organicextracts were dried over Na₂SO₄ and evaporated in vacuo. The residue waspurified by flash column chromatography (BIOTAGE®), eluting with agradient of 0 to 100% EtOAc/hexanes to afford the partially pure(S)-tert-butyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylatecontaminated with triphenylphosphine (77 mg). LC-MS retention time 1.830min; m/z 709.43 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (400 MHz, chloroform-d Partial NMR) δ ppm5.00 (d, J=4.5 Hz, 2H), 3.38-3.52 (m, 4H), 3.10 (br. s, 1H), 2.91 (br s,1H), 2.09-2.33 (m, 4H), 1.93-2.05 (m, 2H), 1.54 (s, 18H).

4-Chloro-2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole

TFA (2 mL) was added to a solution of (S)-tert-butyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(75 mg) in DCM (10 mL) and the mixture was stirred for 2 h at roomtemperature. The solvents were removed in vacuo and the residue wastaken up in a solvent mixture of 1:1 methanol/CH₂Cl₂ and filteredthrough an MCX cartridge (Strata XC). The cartridge was washed withmethanol and the compound was eluted with a solution of NH₃ in methanol(2M). The appropriate fractions were concentrated in vacuo to afford4-chloro-2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole(40 mg, 0.079 mmol) as yellow solid. LC-MS retention time 1.353 min; m/z509.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (500 MHz, MeOD, partially soluble only) δppm 8.20 (s, 1H), 8.09 (s, 1H), 7.88-7.96 (m, 2H), 7.76-7.88 (m, 6H),7.51 (s, 1H), 4.50 (t, J=7.28 Hz, 1H), 4.35 (t, J=7.15 Hz, 1H),3.03-3.31 (partially masked by methanol, m, 4H), 2.24-2.42 (m, 2H),1.88-2.21 (m, 6H).

(S)-tert-Butyl2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

A solution of (S)-tert-butyl2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(402 mg, 0.821 mmol), (S)-tert-butyl2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(344 mg, 0.821 mmol) and sodium bicarbonate (207 mg, 2.46 mmol) in DME(14 mL) and water (1.8 mL) was degassed under vacuum for 10 min. Themixture was heated at 80° C. at which time the flask was opened andPd(Ph₃P)₄ (76 mg, 0.066 mmol) was added. The flask was flushed withnitrogen, sealed and heated at 120° C. for 16 h. The flask was cooled toroom temp., the DME was removed in vacuo and the crude material waspartitioned between DCM and H₂O. The layers were separated and theaqueous layer was extracted several times with DCM. The combined organicextracts were dried over Na₂SO₄ and evaporated in vacuo. The residue waspurified by flash column chromatography (BIOTAGE®), eluting with agradient of 20 to 100% EtOAc/Hexanes and then 0 to 10% methanol/DCM toafford (S)-tert-butyl2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(183 mg). LC-MS retention time 1.543 min; m/z 701.47 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where Solvent A was 10% MeOH/90%H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

(S)-tert-Butyl2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

Manganese(IV) oxide (1.53 g, 17.6 mmol) was added to a solution of(S)-tert-butyl2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(183 mg, 0.196 mmol) in DCM (5 mL) and the mixture was stirred overnightat room temperature. The reaction mixture was filtered through a pad ofdiatomaceous earth (CELITE®) and washed with a solution of methanol/DCM1:1. The volatiles were removed under vacuum using a rotavap to afford(S)-tert-butyl2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(163 mg) as tan solid. LC-MS retention time 1.523 min; m/z 699.53 (MH+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode.

2-((S)-Pyrrolidin-2-yl)-7-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazole

TFA (2 mL, 26.0 mmol) was added in one portion to a stirred solution of(S)-tert-butyl2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(137 mg) in CH₂Cl₂ (10 mL) at room temperature. The mixture was stirredfor 2 h at room temp. and then the solvents were removed in vacuo. Theresidue was taken up in 50% methanol/CH₂Cl₂ and filtered through an MCXcartridge (Strata XC). The cartridge was washed with methanol and thecompound was eluted with a solution of NH₃ in methanol (2M). Theappropriate fractions were concentrated in vacuo to afford2-((S)-pyrrolidin-2-yl)-7-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazole(98 mg, 0.20 mmol) as orange solid. LC-MS retention time 1.245 min; m/z499.30 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.59 (d,J=8.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.13(dd, J=8.6, 1.8 Hz, 1H), 8.01-8.10 (m, 3H), 7.90-7.98 (m, 2H), 7.87 (s,1H), 7.80 (d, J=8.6 Hz, 1H), 5.18 (t, J=7.9 Hz, 1H), 5.05 (t, J=8.1 Hz,1H), 3.63-3.72 (m, 1H), 3.52-3.63 (m, 3H), 2.61-2.77 (m, 2H), 2.45-2.58(m, 2H), 2.33-2.43 (m, 2H), 2.20-2.33 (m, 2H).

(2S,2′S)-tert-Butyl2,2′-(6,6′-(quinoline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate

Pd(Ph₃P)₄ (19.06 mg, 0.016 mmol) was added to a stirred and degassedsolution of 6-bromo-2-chloroquinoline (40 mg, 0.165 mmol),(S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(150 mg, 0.363 mmol) and NaHCO₃ (41.6 mg, 0.495 mmol) in dioxane (1 mL)and H₂O (0.2 mL). The reaction mixture was then heated at 110° C. for 2h., cooled to rt, diluted with MeOH and purified by prep HPLC (H₂O-MeOHwith 0.1% TFA buffer) to yield a TFA salt of (2S,2′S)-tert-butyl2,2′-(6,6′-(quinoline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate(73 mg) as a yellow solid. LC-MS retention time 2.02 min; m/z 700[M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.63-8.74 (1H, m), 8.60(1H, s), 8.44 (1H, dd, J=8.7, 1.6 Hz), 8.38 (1H, br s), 8.32 (1H, d,J=8.8 Hz), 8.25 (2H, d, J=8.8 Hz), 8.14-8.21 (1H, m), 8.04-8.12 (1H, m),7.90-8.00 (2H, m), 5.24-5.36 (2H, m), 3.73-3.83 (2H, m), 3.59-3.72 (2H,m), 2.57-2.74 (2H, m), 2.20-2.33 (2H, m), 2.09-2.20 (4H, m), 1.50 (9H,br s), 1.23 (9H, br s).

2,6-Bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)quino line

TFA (0.25 mL, 3.24 mmol) was added to a solution of a TFA salt of(2S,2′S)-tert-butyl2,2′-(6,6′-(quinoline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))dipyrrolidine-1-carboxylate(65 mg) in DCM (0.5 mL) and the mixture was stirred at rt for 2 h. Thevolatiles were removed under vacuum and the residue was triturated withEt₂O. The resulting solid was collected via filtration and rinsed withEt₂O to yield a TFA salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)quinoline (61mg) as yellow solid. LC-MS retention time 1.12 min; m/z 500 [M+H]⁺.(Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.89 (1H, d, J=8.8 Hz),8.48 (1H, d, J=1.3 Hz), 8.45 (1H, s), 8.34-8.41 (2H, m), 8.31 (1H, d,J=8.8 Hz), 8.12 (1H, dd, J=8.5, 1.8 Hz), 8.09 (1H, s), 7.89 (1H, d,J=8.5 Hz), 7.77-7.85 (2H, m), 5.05-5.19 (2H, m), 3.44-3.72 (4H, m),2.61-2.75 (2H, m), 2.19-2.49 (6H, m).

(1R,3S,5R)-tert-Butyl3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Pd(Ph₃P)₄ (0.382 g, 0.330 mmol) was added to a degassed solution of2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (2.51 g,6.61 mmol), (1R,3S,5R)-tert-butyl3-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.5 g, 6.6 mmol) and sodium carbonate (2.78 g, 33.0 mmol) in DME (52.9mL) and water (13.2 mL) at 80° C. The reaction was backfilled withnitrogen, sealed and heated at 100° C. overnight. The volatiles wereremoved under vacuum and the residue was taken in EtOAc, washed withwater, and the water layer was extracted with EtOAc. The combinedorganic layers were filtered through a pad of diatomaceous earth(CELITE®) and dried over Na₂SO₄, concentrated and purified on a BIOTAGE®(dry loaded on silica gel, charged to a 90 g silica gel cartridge andeluted with a gradient of 0 to 70% ethyl acetate in hexanes, thenflushed with 10% MeOH/DCM) to yield (1R,3S,5R)-tert-butyl3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.8 g, 3.3 mmol, 49% yield) as yellowish solid. LC-MS retention time1.905 min; m/z 552.47 (MH+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where Solvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10%H₂O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode.

tert-Butyl(1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A 200 mL pressure round bottom flask equipped with a magnetic stir barwas charged with (1R,3S,5R)-tert-butyl3-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(795 mg, 1.44 mmol), (1R,3S,5R)-tert-butyl3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (538mg, 1.43 mmol) and sodium bicarbonate (502 mg, 5.97 mmol) in DME (9.5mL) and water (2.4 mL). The solution was degassed under vacuum for 5 minand the reactor was back filled with N₂. Then, Pd(Ph₃P)₄ (110 mg, 0.096mmol) was added under a stream of N₂ and the reactor was sealed and theheated overnight at 120° C. The reaction was cooled to room temperatureand the volatiles were removed under vacuum. The residue was partitionedbetween EtOAc and water and the aqueous layer was extracted with EtOAc.The combined organics were filtered through a pad of diatomaceous earth(CELITE®), dried over Na₂SO₄ and the volatiles were removed undervacuum. The residue was purified by flash column chromatography(BIOTAGE®), eluting with a gradient of 50 to 100% EtOAc/Hexanes and then10% methanol/DCM to afford the partially pure target productcontaminated with starting material, reduced starting material and otherreaction side products. The residue was further purified by prep HPLC(ACN/water, 0.1% TFA) to yield a TFA salt of tert-butyl(1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(200.5 mg). A side product was also collected form the same reactionmixture which was identified as a TFA salt(1R,3S,5R)-3-(5-(6′-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-2,2′-binaphthalen-6-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(108 mg) LC-MS retention time 1.497 min; m/z 673.52 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where Solvent A was 10% MeOH/90%H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.33 (s, 1H), 8.31 (s, 1H),8.09-8.20 (m, 3H), 7.96-8.08 (m, 2H), 7.87-7.94 (m, 2H), 5.07 (t, J=8.2Hz, 1H), 4.91 (m, 1H), 3.69 (br s, 2H), 2.70-2.84 (m, 2H), 2.48 (br s,2H), 1.81-1.94 (m, 2H), 1.51 (br s, 1H), 1.51 (br s, 9H), 1.31 (br s,5H), 1.21 (br s, 4H), 0.89-0.99 (m, 2H), 0.82 (br s, 1H), 0.77 (br s,1H).

(1R,3S,5R)-3-(5-(6′-(2-((1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-2,2′-binaphthalen-6-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Side product obtained as TFA salt (108 mg) after purification of thereaction mixture from Intermediate 85 synthesis. LC-MS retention time1.882 min; m/z 849.84 (MH+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where Solvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10%H₂O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.36 (s, 2H), 8.28 (s, 2H), 8.11-8.19 (m, 6H), 8.03-8.09 (m, 4H),7.87-7.96 (m, 4H), 5.07 (t, J=8.2 Hz, 2H), 3.71 (br s, 2H), 2.75-2.85(m, 2H), 2.51 (br s, 2H), 1.86-1.94 (m, 2H), 1.52 (m, 10H), 1.22 (br s,8H), 0.97 (ddd, J=8.4, 6.0, 5.8 Hz, 2H), 0.83 (br s, 2H).

6-(6-(2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazole

4M HCl in dioxane (10 mL, 40.0 mmol) was added to a stirred solution ofa TFA salt of (1R,3S,5R)-tert-butyl3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-5-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(151 mg) in DCM (3 mL). Precipitate formed immediately. The suspensionwas agitated for 30 min. The volatile components were evaporated undervacuum. The crude residue was taken in DCM (3 mL) and TFA (2 mL) wasadded. The solution was agitated for 1 h. The volatile components wereevaporated under reduced pressure. The residue was taken into MeOH andfiltered through a Strata XC MCX cartridge. The cartridge was washedwith methanol and the compound was release from the cartridge by elutingwith a solution of 2M of ammonia/methanol. The ammonia/methanol filtratewas evaporated under reduced pressure to yield6-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazole(79 mg, 0.17 mmol) as yellow solid. LC-MS retention time 1.130 min; m/z473.35 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.19 (s, 1H), 8.07(s, 1H), 7.92 (dd, J=8.6, 5.8 Hz, 2H), 7.88 (s, 1H), 7.82 (dd, J=5.8,1.5 Hz, 2H), 7.61-7.66 (m, 2H), 7.51 (s, 1H), 4.24-4.35 (m, 2H), 3.11(td, J=6.1, 2.4 Hz, 1H), 3.06 (td, J=6.0, 2.6 Hz, 1H), 2.40-2.53 (m,2H), 2.18-2.33 (m, 2H), 1.69-1.76 (m, 1H), 1.62-1.69 (m, 1H), 0.88 (ddd,J=6.6, 4.3, 2.6 Hz, 1H), 0.79-0.84 (m, 1H), 0.61-0.68 (m, 1H), 0.55-0.60(m, 1H).

6,6′-Bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-5-yl)-2,2′-binaphthyl

TFA (2.0 mL, 26 mmol) was added to a solution of a TFA salt(1R,3S,5R)-3-(5-(6′-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-2,2′-binaphthalen-6-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(108 mg) in DCM (5 mL) and the reaction mixture was stirred for 2 h atrt. The reaction mixture was then concentrated to yield a TFA salt of6,6′-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-5-yl)-2,2′-binaphthyl(22 mg) as tan solid. LC-MS retention time 1.722 min; m/z 649.54 (MH+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.33 (br s, 2H), 8.22(br s, 2H), 8.09-8.15 (m, 4H), 8.01-8.07 (m, 4H), 7.89-7.95 (m, 2H),7.77-7.87 (m, 4H), 4.85-4.98 (m, 2H), 3.51-3.57 (m, 2H), 2.79-2.87 (m,2H), 2.59-2.68 (m, 2H), 2.07-2.14 (m, 2H), 1.23-1.30 (m, 2H), 1.01-1.09(m, 2H).

tert-Butyl(1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-1,5-naphthyridin-2-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (17.4 mg, 0.015 mmol) was addedto a solution of 2,6-dichloro-1,5-naphthyridine (30 mg, 0.151 mmol),sodium bicarbonate (38.0 mg, 0.452 mmol) and (1R,3S,5R)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(141 mg, 0.332 mmol) in dioxane (1.0 mL) and H₂O (0.2 mL) and themixture was heated and stirred at 110° C. for 2 h. The reaction wasdiluted with MeOH, filtered, concentrated and purified by prep HPLC(H₂O-MeOH with 10 mM NH₄OAc buffer) to yield tert-butyl(1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-1,5-naphthyridin-2-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22.3 mg, 0.030 mmol) as a white solid. LC-MS retention time 2.11 min;m/z 725 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90%water:10% methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1%TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3min. Wavelength=220).

2,6-Bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridine

TFA (0.25 mL, 3.2 mmol) was added to a solution of tert-butyl(1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-1,5-naphthyridin-2-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(20 mg, 0.028 mmol) in DCM (0.5 mL) and the mixture was stirred at rtfor 16 h. The volatile were removed under vacuum and the residue wastriturated with Et₂O. The resulting solid was collected via filtrationand rinsed with Et₂O to yield a TFA salt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridine(26 mg, 0.022 mmol, 78% yield) as a yellow solid. LC-MS retention time1.41 min; m/z 525 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10.Solvent A=90% water:10% methanol: 0.1% TFA. Solvent B=10% water:90%methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100.Gradient Time=3 min. Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.61(2H, d, J=8.8 Hz), 8.51 (2H, s), 8.40 (2H, d, J=9.0 Hz), 8.23 (2H, dd,J=8.5, 1.5 Hz), 7.81 (2H, d, J=8.5 Hz), 4.74-4.97 (2H, m), 3.47-3.57(2H, m), 2.78-2.88 (2H, m), 2.52-2.65 (2H, m), 2.04-2.15 (2H, m),1.22-1.33 (2H, m), 0.99-1.11 (2H, m).

tert-Butyl(1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-5-chloro-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

NCS (20 mg, 0.15 mmol) was added portionwise to a stirring solution oftert-butyl(1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(183 mg, 0.272 mmol) in DMF (5 mL) at rt. The reaction mixture was thenheated at 50° C. for 3 h. The reaction was cooled to 0° C., additionalNCS (15 mg, 0.112 mmol) was added, and the mixture was stirred for 2 hat 50° C. The reaction was diluted with water (2 mL) and methanol (2mL), the volatiles were removed and the crude product was purified byprep HPLC (TFA) to yield a TFA salt of tert-butyl(1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-5-chloro-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(140.4 mg) as orange solid. LC-MS retention time 1.822 min; m/z 707.54(1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm 5 μm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.27(d, J=2.8 Hz, 2H), 8.03-8.18 (m, 4H), 7.87-7.98 (m, 3H), 5.04-5.10 (m,1H), 4.63 (d, J=7.6 Hz, 1H), 3.71 (br s, 1H), 3.63 (br s, 1H), 2.74-2.87(m, 1H), 2.59 (dd, J=13.3, 8.7 Hz, 1H), 2.51 (br s, 1H), 2.41 (ddd,J=13.6, 6.7, 6.6 Hz, 1H), 1.86-1.95 (m, 1H), 1.78 (br s, 1H), 1.12-1.63(m, 18H), 0.97 (ddd, J=8.7, 6.0, 5.8 Hz, 1H), 0.79-0.91 (m, 2H), 0.66(br s, 1H).

2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hex-3-yl)-5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-4-chloro-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazole

TFA (2 mL, 26.0 mmol) was added to a solution of a TFA salt oftert-butyl(1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-5-chloro-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(131 mg, 0.140 mmol) in DCM (10 mL) and the mixture was stirred for 3 hat rt. The volatiles were removed under vacuum and the residue was takeninto MeOH and filtered through a Strata XC MCX cartridge. The cartridgewas washed with methanol and the compound was release from the cartridgeby eluting with a solution of 2M of ammonia/methanol. Theammonia/methanol filtrate was evaporated under reduced pressure to yield2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-4-chloro-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazole(55 mg, 0.11 mmol) as tan solid. LC-MS retention time 1.375 min; m/z507.33 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm 5 μm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.26(s, 1H), 8.19 (s, 1H), 8.00-8.09 (m, 3H), 7.92 (ddd, J=12.1, 8.6, 1.8Hz, 2H), 7.85 (dd, J=8.6, 1.5 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 4.96 (dd,J=11.0, 7.6 Hz, 1H), 4.64 (app t, J=9.3 Hz, 1H), 3.53-3.59 (m, 1H),3.44-3.50 (m, 1H), 2.82 (dd, J=13.0, 7.5 Hz, 1H), 2.61-2.74 (m, 3H),2.03-2.15 (m, 2H), 1.24-1.30 (m, 1H), 1.18-1.24 (m, 1H), 0.96-1.09 (m,2H).

(1R,3S,5R)-3-(2-(3-Bromophenyl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

DIPEA (2.79 mL, 16.0 mmol) was added to a stirring slurry of(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (2.00 g, 8.80 mmol) and 2-bromo-1-(3-bromophenyl)ethanone (2.22 g,8.00 mmol) in acetonitrile (25 mL) (the solution became clear and ambercolored) and the reaction mixture was stirred overnight. The reactionwas concentrated and purified via BIOTAGE® (80 g SiO₂, 10-25%EtOAc/hexanes) to yield (1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl)2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.37 g, 7.94mmol) as a viscous light yellow oil. LC-MS retention time 1.853 min; m/z423 and 425.98 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a waters XTERRA® MS 7 u C18 3.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where Solvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate andSolvent B was 5% H₂O/95% MeOH/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.04 (d, J=1.8 Hz, 1H), 7.83 (d, J=7.8 Hz,1H), 7.75 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.0, 7.8 Hz, 1H), 5.58-5.10 (m,2H), 4.23 (br s, 1H), 3.62-3.39 (m, 1H), 2.58 (dt, J=13.3, 6.5 Hz, 1H),2.46 (dd, J=13.3, 9.5 Hz, 1H), 1.73-1.51 (m, 1H), 1.47 (s, 9H), 0.85 (brs, 1H), 0.51 (s, 1H).

(1R,3S,5R)-tert-Butyl3-(4-(3-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

In a 350 mL high pressure vessel ammonium acetate (5.94 g, 77 mmol) wasadded to a solution of (1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl)2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.33 g, 7.85mmol) in xylene (75 mL) and stirred under nitrogen for 5 minutes. Thevessel was sealed and then placed into an oil bath which had been heatedto 140° C. (reaction became dark brown) and the reaction was held at140° C. for 11 h. Additional ammonium acetate (3.0 g) was added and thereaction was stirred at 145° C. for 8 hrs, cooled to rt and stirred(>90% conversion by LC-MS). The reaction was concentrated under highvacuum to a brown oil which was partitioned between DCM (˜200 mL) and ½sat. sodium bicarbonate (˜200 mL). The organic layer was dried (MgSO₄),filtered and concentrated. The crude orange solidified foam was purifiedon a BIOTAGE® Horizon (20-50% EtOAc/hexanes, 160 g SiO₂) to yield(1R,3S,5R)-tert-butyl3-(4-(3-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.03 g, 5.02 mmol) as a yellow solidified foam. LC-MS retention time2.450 min; m/z 404 and 406.06 (1:1) (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 5% MeOH/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mM ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.89 (s, 1H), 7.65 (d,J=6.5 Hz, 1H), 7.42-7.32 (m 2H), 7.26 (t, J=7.8 Hz, 1H), 4.72-4.61 (m,1H), 3.62-3.53 (m, 1H), 2.51 (dd, J=13.0, 7.8 Hz, 1H), 2.36-2.26 (m,1H), 1.75-1.66 (m, 1H), 1.29 (br s, 9H), 0.84 (dt, J=8.0, 5.7 Hz, 1H),0.63-0.57 (m, 1H).

tert-Butyl (1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A solution of (1R,3S,5R)-tert-butyl3-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(220 mg, 0.395 mmol) (prepared in the same manner as Intermediate 51from Intermediate 55), (1R,3S,5R)-tert-butyl3-(4-(3-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(192 mg, 0.474 mmol) and cesium carbonate (386 mg, 1.185 mmol) in THF (4mL) and water (4 mL) in a 100 mL pressure flask was degassed undervacuum for 5 min and then backfilled with nitrogen. Palladium (II)acetate (8.9 mg, 0.039 mmol) was added and the mixture was heated for 4h at 120° C. The reaction mixture was cooled to RT, diluted with waterand extracted with EtOAC and DCM. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated. The cruderesidue was purified on a BIOTAGE® system (90 g silica gel cartridge,eluted with a gradient of 0 to 100% EtOAc in hexanes) to yieldtert-butyl(1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(142 mg, 0.203 mmol) as a yellow solid. LC-MS retention time 1.585 min;m/z 699.57 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm Sum columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.33(d, J=1.2 Hz, 1H), 8.31 (s, 1H), 8.20-8.24 (m, 1H), 8.14-8.20 (m, 1H),8.10-8.14 (m, 1H), 7.97-8.07 (m, 3H), 7.94 (d, J=7.9 Hz, 1H), 7.87-7.92(m, 1H), 7.77-7.82 (m, 1H), 7.67-7.74 (m, 1H), 4.84-4.96 (m, 2H), 3.67(br s, 2H), 2.69-2.80 (m, 2H), 2.47 (br s, 2H), 1.82-1.91 (m, 2H),1.19-1.63 (m, 18H), 0.89-0.97 (m, 2H), 0.77 (br s, 2H).

(1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-Azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

TFA (2 mL, 26.0 mmol) was added to a solution of tert-butyl(1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(130 mg, 0.20 mmol) in DCM (2 mL) and the mixture was stirred for 2 h atRT. The volatiles were removed under vacuum and the crude product waspurified by prep HPLC (methanol/water, 0.1% TFA) to yield a TFA salt of(1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(103 mg) as a tan solid. LC-MS retention time 1.303 min; m/z 499.13(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire C18 4.6×30 mm 5 μM column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.33(s, 1H), 8.22 (d, J=12.5 Hz, 2H), 8.02 (dd, J=8.6, 5.8 Hz, 2H),7.90-7.97 (m, 2H), 7.75-7.82 (m, 4H), 7.58 (t, J=7.8 Hz, 1H), 4.74-4.78(m, 2H), 3.46-3.53 (m, 2H), 2.64-2.74 (m, 4H), 2.04-2.12 (m, 2H),1.19-1.26 (m, 2H), 1.02 (ddd, J=14.2, 7.3, 7.2 Hz, 2H).

(1R,3S,5R)-tert-Butyl3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Pd(Ph₃P)₄ (28.5 mg, 0.025 mmol) was added to a degassed solution of6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol), (1R,3S,5R)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(115 mg, 0.271 mmol) and sodium bicarbonate (62.1 mg, 0.739 mmol) indioxane (1 mL) and H₂O (0.2 mL) and the mixture was stirred at 110° C.for 2 h and then at 120° C. for 2 h. The reaction was diluted with MeOH,filtered and purified by prep HPLC (H₂O-MeOH with 10 mM NH₄OAc buffer)to yield (1R,3S,5R)-tert-butyl3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(102.2 mg, 0.202 mmol, 82% yield) as bright yellow solid. LC-MSretention time 2.31 min; m/z 506 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50mm S10. Solvent A=90% water:10% methanol: 0.1% TFA. Solvent B=10%water:90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final %B=100. Gradient Time=3 min. Wavelength=220).

2-(2-((1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronicacid

Pd(Ph₃P)₄ (23.28 mg, 0.020 mmol) was added to a degassed solution of(1R,3S,5R)-tert-butyl3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(102 mg, 0.201 mmol), KOAc (49.4 mg, 0.504 mmol) andbis(pinacolato)diboron (113 mg, 0.443 mmol) in dioxane (2 mL) and thereaction was stirred at 83° C. for 16 h. The reaction mixture waspartitioned between EtOAc (20 mL) and sat. NH₄Cl(aq.) (5 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated to an orangeoil, which was purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronicacid (57 mg, 0.121 mmol, 60.0% yield) as orange solid. LC-MS retentiontime 1.94 min; m/z 472 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10.Solvent A=90% water:10% methanol: 0.1% TFA. Solvent B=10% water:90%methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100.Gradient Time=3 min. Wavelength=220).

tert-Butyl(1R,3S,5R)-3-(4-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-6-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Pd(OAc)₂ (2.67 mg, 0.012 mmol) was added to a degassed solution of2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronicacid (56 mg, 0.119 mmol), (1R,3S,5R)-tert-butyl3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(66.9 mg, 0.178 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (9.76 mg, 0.024mmol) and K₂CO₃ (49.3 mg, 0.356 mmol) in THF (1 mL) and water (0.25 mL)and the mixture was stirred at 120° C. for 2 h. The reaction was dilutedwith MeOH, filtered and purified by prep HPLC (H₂O-MeOH with 10 mMNH₄OAc buffer) to yield (1R,3S,5R)-tert-butyl3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(32 mg, 0.047 mmol) as yellow solid. LC-MS retention time 1.89 min; m/z675 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=95%water/5% methanol/10 mM ammonium acetate. Solvent B=5% water/95%methanol/10 mM ammonium acetate. Flow Rate=4 mL/min. Start % B=0. Final% B=100. Gradient Time=2 min. Wavelength=220). ¹H NMR (400 MHz, MeOD) δppm 9.44 (s, 1H), 8.45 (br s, 1H), 8.39 (s, 1H), 8.23 (d, J=8.8 Hz, 1H),8.18 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.69-7.76 (m, 1H), 7.64(s, 1H), 4.69-4.78 (m, 1H), 4.49-4.57 (m, 1H), 3.56-3.70 (m, 2H),2.50-2.73 (m, 2H), 2.31-2.47 (m, 2H), 1.67-1.86 (m, 2H), 1.31 (br s,18H), 0.82-0.95 (m, 2H), 0.54-0.75 (m, 2H).

2-(2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)quinoxaline

TFA (0.25 mL, 3.24 mmol) was added to a solution of(1R,3S,5R)-tert-butyl3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(30 mg, 0.044 mmol) in DCM (0.5 mL) and the mixture was stirred at rtfor 16 h. The volatiles were removed under vacuum and the residue wastriturated with Et₂O to yield a TFA salt of2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline(32.7 mg) as yellow solid. LC-MS retention time 1.33 min; m/z 475[M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 9.47 (s, 1H), 8.54 (s,1H), 8.50 (s, 1H), 8.31 (dd, J=8.8, 1.8 Hz, 1H), 8.26 (dd, J=8.5, 1.3Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.82 (d, J=8.8 Hz, 1H),4.85-4.97 (m, 1H), 4.67 (dd, J=10.8, 7.5 Hz, 1H), 3.45-3.57 (m, 2H),2.77-2.86 (m, 1H), 2.65-2.74 (m, 1H), 2.52-2.65 (m, 2H), 2.02-2.15 (m,2H), 1.18-1.30 (m, 2H), 0.95-1.09 (m, 2H).

(1R,3S,5R)-3-(4-Iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

TFA (1 mL, 12.98 mmol) was added dropwise to a solution of(1R,3S,5R)-tert-butyl3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (450mg, 1.20 mmol) in DCM (5 mL) at room temperature. The mixture wasstirred for 2 h at room temperature, then, the volatiles were removedand the residue was taken in MeOH (5 mL) and filtered through a StrataXC MCX cartridge. The cartridge was washed with methanol (30 mL) and thecompound was release from the cartridge by eluting with a solution of 2Mof ammonia/methanol (40 mL) and concentrated to give(1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (283mg, 1.03 mmol, 86% yield) as white solid. LC-MS retention time 0.448min; m/z 275.94 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm column usinga SPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 7.17(s, 1H), 4.20 (dd, J=10.4, 7.3 Hz, 1H), 3.08 (td, J=6.2, 2.6 Hz, 1H),2.38 (dd, J=12.5, 7.3 Hz, 1H), 2.19 (ddd, J=12.7, 10.5, 4.9 Hz, 1H),1.68-1.74 (m, 1H), 0.85 (ddd, J=6.6, 4.4, 2.8 Hz, 1H), 0.61-0.67 (m,1H).

Methyl(S)-1-((1R,3S,5R)-3-(4-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HATU (464 mg, 1.22 mmol) was added to a solution of(1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (280mg, 1.02 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (214mg, 1.22 mmol) and DIEA (1.8 mL, 10 mmol) in DMF (3 mL). The reactionmixture was stirred 2 h at room temperature and then diluted with MeOH(5 mL) and water (5 mL). The volatiles were removed under vacuum and theresidue was purified with flash chromatography (sample was dry loaded onsilica gel and eluted with 0-100 ethyl acetate/hexanes) to afford methyl(S)-1-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(500 mg, 0.925 mmol, 91% yield) as yellowish oil. LC-MS retention time0.850 min; m/z 432.97 (MH+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 7.09(s, 1H), 5.09 (dd, J=8.9, 4.6 Hz, 1H), 4.47-4.60 (m, 1H), 3.67 (s, 3H),3.59-3.62 (m, 1H), 2.39-2.49 (m, 1H), 2.29-2.39 (m, 1H), 2.12 (dq,J=13.6, 6.8 Hz, 1H), 1.95-2.06 (m, 1H), 1.11 (dt, J=8.6, 5.5 Hz, 1H),0.94-1.02 (m, 3H), 0.91 (d, J=6.7 Hz, 3H), 0.76 (br s, 1H).

(1R,3S,5R)-tert-Butyl3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A solution of (1R,3S,5R)-tert-butyl3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(573 mg, 1.04 mmol), methyl(S)-1-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(374 mg, 0.87 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(SPHOS, 71.0 mg, 0.173 mmol) and cesium carbonate (846 mg, 2.60 mmol) inTHF (7.9 mL) and water (0.8 mL) was degassed at 0° C. under vacuum for 5min and the reactor was then back filled with nitrogen. Palladium(II)acetate (19.4 mg, 0.087 mmol) was added and the reaction mixture washeated at 100° C. for 3 h. water was added to the cooled solution andthe reaction was further diluted with EtOAc (15 mL). The phases wereseparated and the aqueous layer was extracted with EtOAc (15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered through a padof diatomaceous earth (CELITE®) and the volatiles were removed underreduced pressure. The residue was purified with flash chromatography(sample was dry loaded on silica gel and eluted with 20-100% ethylacetate/hexanes then 5% MeOH/DCM) to afford (1R,3S,5R)-tert-butyl3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(246 mg, 0.337 mmol, 39.0% yield). LC-MS retention time 1.448 min; m/z730.21 (MH+).LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm column usinga SPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.32(br s, 1H), 8.30 (s, 1H), 8.03-8.19 (m, 4H), 7.96-8.03 (m, 1H), 8.01 (s,1H), 7.85-7.96 (m, 2H), 5.18 (dd, J=9.0, 7.0 Hz, 1H), 5.09 (dd, J=8.9,7.6 Hz, 1H), 4.58 (d, J=6.5 Hz, 1H), 3.81-3.89 (m, 1H), 3.65-3.75 (m,1H), 3.69 (s, 3H), 2.68-2.86 (m, 2H), 2.52 (dt, J=13.6, 6.8 Hz, 2H),2.15-2.29 (m, 1H), 2.06-2.15 (m, 1H), 1.85-1.95 (m, 1H), 1.51 (br s,4H), 1.41 (d, J=16.3 Hz, 1H), 1.27 (s, 1H), 1.20 (br s, 3H), 1.12 (ddd,J=8.7, 6.0, 5.9 Hz, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.87-1.00 (m, 5H), 0.83(br s, 1H).

Methyl(S)-1-((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

TFA (2 mL), was added to a solution of (1R,3S,5R)-tert-butyl3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(226 mg, 0.310 mmol) in DCM (5 mL) and the reaction was stirred for 2 hat room temperature. The solution was concentrated under vacuum and theresidue was taken in MeOH (10 mL) and filtered through a Strata XC MCXcartridge and washed with methanol (25 mL). The compound was releasedfrom the cartridge by washing the column with a solution of 2M ofammonia/methanol (10 mL) and concentrated under reduced pressure to givea methyl(S)-1-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(131 mg, 0.208 mmol) as tan solid. LC-MS retention time 1.235 min; m/z630.17 (MH+).LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm column usinga SPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.16(s, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.3, 6.3 Hz, 2H), 7.87 (s, 1H),7.78-7.85 (m, 2H), 7.60-7.69 (m, 2H), 7.44 (s, 1H), 5.20 (dd, J=8.8, 4.8Hz, 1H), 4.62 (d, J=6.8 Hz, 1H), 4.28 (dd, J=9.8, 7.8 Hz, 1H), 3.66-3.76(m, 4H), 3.35-3.41 (m, 2H), 3.03 (td, J=6.0, 2.5 Hz, 1H), 2.40-2.59 (m,3H), 2.12-2.25 (m, 2H), 1.99-2.09 (m, 1H), 1.59-1.68 (m, 1H), 1.10-1.18(m, 1H), 1.00-1.08 (m, 3H), 1.04 (d, J=6.8 Hz, 3H), 0.91-1.04 (m, 1H),0.95 (d, J=6.8 Hz, 3H), 0.76-0.84 (m, 2H), 0.50-0.59 (m, 1H).

Methyl(S)-2-((1R,3S,5R)-3-(4-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

HATU (846 mg, 2.23 mmol) was added to a solution of(1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (510mg, 1.85 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(483 mg, 2.23 mmol) and DIEA (3.24 mL, 18.5 mmol) in DMF (5 mL) and thereaction was stirred 2 h at room temperature. The reaction mixture wasdiluted with MeOH (5 mL) and water (5 mL). The volatiles were removedunder vacuum and the residue was purified with flash chromatography(sample was dry loaded on silica gel and eluted with 0-100% ethylacetate/hexanes then 10% MeOH/DCM) to afford the methyl(S)-2-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate(370 mg, 0.780 mmol, 42.1% yield) as white foam. Impure material wasfurther purified on reverse phase HPLC (water/methanol, 0.1% TFA) toafford the TFA salt of methyl(S)-2-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate,(387 mg) as colorless oil. LC-MS retention time 0.690 min; m/z 474.95(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90%methanol/0.1% TFA. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 7.58(s, 1H), 5.04 (dd, J=9.2, 6.7 Hz, 1H), 4.56 (d, J=7.8 Hz, 1H), 3.96 (td,J=11.7, 3.1 Hz, 2H), 3.74-3.81 (m, 1H), 3.65-3.73 (m, 3H), 3.35-3.44 (m,2H), 2.61 (dd, J=13.6, 9.3 Hz, 1H), 2.37 (ddd, J=13.6, 6.7, 6.5 Hz, 1H),1.96-2.09 (m, 2H), 1.37-1.62 (m, 4H), 1.06 (dt, J=8.8, 5.9 Hz, 1H), 0.84(td, J=5.6, 2.4 Hz, 1H).

(1R,3S,5R)-tert-Butyl3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A slurry of (1R,3S,5R)-tert-butyl3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(407 mg, 0.738 mmol), a TFA salt of methyl(S)-2-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate(350 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (60.6 mg,0.148 mmol) and cesium carbonate (721 mg, 2.21 mmol) in THF (6.7 mL) andwater (0.7 mL) was degassed at 0° C. under vacuum for 5 min and then thereactor was back filled with nitrogen. Palladium(II) acetate (16.6 mg,0.074 mmol) was added and the mixture was heated at 100° C. for 3 h. Thevolatiles were removed under vacuum and the mixture was diluted withwater (20 mL) and EtOAc (20 mL). The phases were separated and theaqueous layer was extracted with EtOAc (20 mL). The combined organiclayers were dried over Na₂SO₄, filtered and evaporated under vacuum. Theresidue was purified with flash chromatography (sample was dry loaded onsilica gel and eluted with 20-100% ethyl acetate/hexanes, then 10%MeOH/DCM). The residue was purified again by on reverse phase HPLC(water/methanol, 0.1% TFA) to afford the TFA salt of(1R,3S,5R)-tert-butyl3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(231 mg) as yellow solid. LC-MS retention time 1.395 min; m/z 772.31(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90%methanol/0.1% TFA. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.31(s, 2H), 8.09-8.18 (m, 3H), 8.05 (dd, J=8.7, 1.7 Hz, 1H), 7.97-8.02 (m,2H), 7.91 (d, J=8.6 Hz, 1H), 7.88 (dd, J=8.7, 1.7 Hz, 1H), 5.16 (dd,J=9.2, 7.0 Hz, 1H), 5.01-5.09 (m, 1H), 4.62 (d, J=7.6 Hz, 1H), 3.91-4.02(m, 3H), 3.83-3.89 (m, 1H), 3.70 (br s, 4H), 3.35-3.45 (m, 2H),2.68-2.83 (m, 2H), 2.45-2.57 (m, 2H), 2.04-2.16 (m, 2H), 1.90 (br s,1H), 1.43-1.61 (m, 8H), 1.14-1.31 (m, 4H), 1.07-1.13 (m, 1H), 0.97 (dt,J=8.8, 5.8 Hz, 1H), 0.91 (br s, 1H), 0.82 (br s, 1H).

Methyl(S)-2-((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

TFA (2 mL, 26.0 mmol) was added to a solution of a TFA salt of(1R,3S,5R)-tert-butyl3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(150 mg) in DCM and the mixture was stirred for 2 h at rt. The volatileswere removed under vacuum and the residue was taken in MeOH (15 mL),filtered through a Strata XC MCX cartridge (1 g) and washed withmethanol. The compound was release from the cartridge by washing thecolumn with a solution of 2M of ammonia/methanol (20 mL) andconcentrated to give methyl(S)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate(100 mg, 0.149 mmol) as white solid. LC-MS retention time 1.772 min; m/z670.36 (M−H+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm column usinga SPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/10 mM ammonium acetate and solventand Solvent B was 10% water/90% methanol/10 mM ammonium acetate andsolvent. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.28 (s, 1H),8.24 (s, 1H), 8.13 (d, J=8.9 Hz, 1H), 8.05-8.10 (m, 1H), 8.03 (s, 1H),7.96-8.00 (m, 2H), 7.84 (dd, J=8.7, 1.7 Hz, 1H), 7.75-7.82 (m, 2H), 5.16(dd, J=9.2, 7.3 Hz, 1H), 4.84-4.88 (partially shaded by MeOD, m, 1H),4.62 (d, J=7.6 Hz, 1H), 3.91-4.01 (m, 2H), 3.84-3.89 (m, 1H), 3.66-3.76(m, 3H), 3.51-3.56 (m, 1H), 3.35-3.46 (m, 2H), 2.82 (dd, J=12.8, 7.3 Hz,1H), 2.73 (dd, J=13.7, 9.2 Hz, 1H), 2.61 (td, J=12.0, 4.7 Hz, 1H), 2.53(ddd, J=13.8, 6.8, 6.6 Hz, 1H), 2.06-2.16 (m, 3H), 1.58-1.64 (m, 1H),1.44-1.57 (m, 3H), 1.23-1.30 (m, 1H), 1.08-1.16 (m, 1H), 1.05 (q, J=7.8Hz, 1H), 0.88-0.93 (m, 1H).

6-Bromo-2-(1-ethoxyvinyl)quinoxaline

Dichlorobis(triphenylphosphine)-palladium(II) (17.30 mg, 0.025 mmol) wasadded to a solution of 6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol)and tributyl(1-ethoxyvinyl)stannane (107 mg, 0.296 mmol) in dioxane (1.5mL) and the mixture was stirred at 110° C. for 2 h. The reaction wasdiluted with MeOH, and purified by prep HPLC (H₂O-MeOH with 10 mM NH₄OAcbuffer) to yield 6-bromo-2-(1-ethoxyvinyl)quinoxaline (36 mg, 0.129mmol, 52.3% yield) as white solid. LC-MS retention time 2.76 min; m/z279 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90%water:10% methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1%TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3min. Wavelength=220).

2-Bromo-1-(6-bromoquinoxalin-2-yl)ethanone

NBS (55.1 mg, 0.310 mmol) was added to a solution of6-bromo-2-(1-ethoxyvinyl)quinoxaline (72 mg, 0.26 mmol) in THF (2 mL)and water (0.500 mL) and the mixture was stirred at rt for 2 h. Thereaction was diluted with MeOH and purified by prep HPLC (H₂O-MeOH with10 mM NH₄OAc buffer) to yield 2-bromo-1-(6-bromoquinoxalin-2-yl)ethanone(50 mg, 0.15 mmol, 59% yield) as white solid. LC-MS retention time 2.40min; m/z 329 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. SolventA=90% water:10% methanol: 0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. GradientTime=3 min. Wavelength=220).

(1S,3S,5S)-3-(2-(6-Bromoquinoxalin-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

DIPEA (0.040 mL, 0.227 mmol) was added to a solution of2-bromo-1-(6-bromoquinoxalin-2-yl)ethanone (50 mg, 0.152 mmol) and(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (37.9 mg, 0.167 mmol) in acetonitrile (1.5 mL) and the mixture wasstirred at rt for 16 h. The solvent was evaporated and the residue waspartitioned between EtOAc (20 mL)/aq. sat. NaHCO₃ (5 mL). The organiclayer was dried (MgSO₄), filtered and concentrated to yield crude(1R,3S,5R)-3-(2-(6-bromoquinoxalin-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (63 mg) as orange solid.LC-MS retention time 2.74 min; m/z 476 [M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10% methanol: 0.1% TFA. Solvent B=10%water:90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final %B=100. Gradient Time=3 min. Wavelength=220).

(1R,3S,5R)-tert-Butyl3-(4-(6-bromoquinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

NH₄OAc (102 mg, 1.323 mmol) was added to a solution of(1R,3S,5R)-3-(2-(6-bromoquinoxalin-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (63 mg, 0.13 mmol) intoluene (3 mL) and the mixture was stirred at 120° C. for 4 h.Additional NH₄OAc (102 mg, 1.323 mmol) was added and the reaction wasfurther heated at 120° C. for 4 h. The reaction was diluted with EtOAc(20 mL) and aq. sat. NaHCO₃ (5 mL). The organic layer was dried (MgSO₄),filtered, concentrated and then purified by flash silica chromatography(eluted with 1:2 EtOAc/hexane) to yield (1R,3S,5R)-tert-butyl3-(4-(6-bromoquinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(25 mg, 0.055 mmol) as red orange solid. LC-MS retention time 2.07 min;m/z 456 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90%water:10% methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1%TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3min. Wavelength=220).

(1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Pd(OAc)₂ (1.230 mg, 5.48 μmol) was added to a degassed suspension of(1R,3S,5R)-tert-butyl3-(4-(6-bromoquinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(25 mg, 0.055 mmol), K₂CO₃ (22.71 mg, 0.164 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (4.50 mg, 10.96μmol) and (1R,3S,5R)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(30.3 mg, 0.071 mmol) in THF (1 mL) and water (0.250 mL) and the mixturewas stirred at 110° C. for 2 h. The reaction was diluted with MeOH,filtered and purified by prep HPLC (H₂O-MeOH with 10 mM NH₄OAc buffer)to yield (1R,3S,5R)-tert-butyl3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(12 mg, 0.018 mmol, 33% yield) as yellow solid. LC-MS retention time1.90 min; m/z 675 [M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10.Solvent A=95% water/5% methanol/10 mM ammonium acetate. Solvent B=5%water/95% methanol/10 mM ammonium acetate. Flow Rate=4 mL/min. Start %B=0. Final % B=100. Gradient Time=2 min. Wavelength=220). ¹H NMR (400MHz, MeOD) δ ppm 9.38 (s, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.16-8.22 (m,1H), 8.10-8.15 (m, 1H), 7.95 (s, 2H), 7.66-7.76 (m, 2H), 3.54-3.73 (m,2H), 2.52-2.69 (m, 2H), 2.33-2.47 (m, 2H), 1.71-1.84 (m, 2H), 1.08-1.57(m, 20H), 0.83-0.95 (m, 2H), 0.60-0.74 (m, 2H).

6-(2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)quinoxaline

TFA (0.25 mL, 3.24 mmol) was added to a solution of(1R,3S,5R)-tert-butyl3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(10 mg, 0.015 mmol) in DCM (0.5 mL) and the mixture was stirred at rtfor 16 h. The volatiles were removed under vacuum and the residue wastriturated with Et₂O. The resulting solid was rinsed with Et₂O to yielda TFA salt of6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline(10.5 mg) as yellow solid. LC-MS retention time 1.32 min; m/z 475[M+H]⁺. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220).

Benzyl(2S)-2-(6-(6-(2-((2S)-1-((benzyloxy)carbonyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyridin-6-yl)-2-naphthyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-pyrrolidinecarboxylate

Prepared in a similar manner as Intermediate 39 using(S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid as a startingmaterial rather than (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid and the intermediates were not SEM protected. Prepared benzyl(2S)-2-(6-(6-(2-((2S)-1-((benzyloxy)carbonyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyridin-6-yl)-2-naphthyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-pyrrolidinecarboxylate(20.8 mg) as a white solid. LC-MS retention time 1.742 min; m/z 769.41(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and SolventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

1-(4-(6-Acetylnaphthalen-2-yl)phenyl)ethanone

A solution of sodium carbonate (5.43 g, 51.3 mmol) in water (35 mL) wasadded to a stirred solution of 1-(6-bromonaphthalen-2-yl)ethanone (2.554g, 10.25 mmol) and 4-acetylphenylboronic acid (2.017 g, 12.30 mmol) intoluene (35.0 mL) and ethanol (35.0 mL) and nitrogen was bubbled throughthe reaction mixture for 15 min. Then Pd(PPh₃)₄ (0.237 g, 0.205 mmol)was added, and the reaction was flushed with nitrogen and heated at 95°C. under nitrogen for 8 h and then stirred overnight at rt. The reactionwas concentrated to dryness under high vacuum and then partitionedbetween DCM (˜200 mL) and water (˜150 mL). The organic layer was thenwashed with brine (˜100 mL), dried (MsSO₄), filtered and concentrated.The residue was triturated with MeOH (˜120 mL) and the remaining solidswere redissolved into DCM and concentrated to dryness (˜2.7 g of orangesolid). This material was dissolved into hot EtOAc (80 mL) and allowedto cool. The resulting solids were collected by filtration and rinsedwith Et₂O to yield 1-(4-(6-acetylnaphthalen-2-yl)phenyl)ethanone (1.84g). LC-MS retention time 2.443 min; m/z 288.98 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.51(s, 1H), 8.05-8.16 (m, 5H), 7.98 (d, J=8.8 Hz, 1H), 7.81-7.88 (m, 3H),2.76 (s, 3H), 2.68 (s, 3H).

2-Bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone

A solution of bromine (0.669 mL, 13.0 mmol) in DCM (10 mL) was added toa stirred solution of 1-(4-(6-acetylnaphthalen-2-yl)phenyl)ethanone(1.827 g, 6.34 mmol) in DCM (30 mL) and the reaction was stirred at rtfor 1 d. The reaction mixture was diluted with DCM (˜20 mL) andconcentrated to dryness to yield2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (2.83 g)which was used without further purification. LC-MS retention time 2.708min; m/z 446.71 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.57 (s, 1H), 8.07-8.17 (m, 5H), 8.02 (d, J=8.8 Hz,1H), 7.88 (d, J=8.8 Hz, 3H), 4.60 (s, 2H), 4.51 (s, 2H).

(2S,5S)-2-(2-(4-(6-(2-((2S,5S)-1-(tert-Butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate

Hunig's Base (1.662 mL, 9.52 mmol) was added to a stirred slurry of2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (1.42 g,3.17 mmol) and(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(1.45 g, 6.34 mmol) in acetonitrile (60 mL). The reaction was stirred atrt for 1 d (slowly became clear) and the clear orange solution wasconcentrated and purified on a BIOTAGE® Horizon (160 g SiO₂, 30-40%EtOAc/hexanes) to yield(2S,5S)-2-(2-(4-(6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (1.81 g) as anoff-white solidified foam. LC-MS retention time 3.126 min; m/z 765.87(M+Na). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, chloroform-d) δ ppm 8.48 (s, 1H), 8.13 (s, 1H), 7.99-8.11 (m, 5H),7.86 (d, J=8.3 Hz, 3H), 5.24-5.76 (m, 4H), 4.41-4.59 (m, 2H), 3.93-4.11(m, 2H), 2.28-2.42 (m, 4H), 2.11 (br. s., 2H), 1.77 (br. s., 2H), 1.49(br. s., 9H), 1.48 (br. s., 9H), 1.35 (br. s., 6H).

tert-Butyl(2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinecarboxylate

Ammonium acetate (3.76 g, 48.7 mmol) was added to a stirred solution of(2S,5S)-2-(2-(4-(6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (1.81 g, 2.437 mmol)in toluene (40 mL) and the slurry was stirred at rt for 10 min beforebeing heated at 100° C. for 12 h. The reaction was cooled to rt,concentrated to dryness and the residue was partitioned between DCM(˜150 mL) and ½ sat NaHCO₃ (aq) (˜150 mL). The organic layer was washedwith brine (˜100 mL), dried (MgSO₄), filter and concentrated to asolidified brown foam which was purified by BIOTAGE® Horizon (160 gSiO₂, 1.5-3% MeOH/DCM) to yield tert-butyl(2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinecarboxylate(1.46 g) as a yellow-orange solidified foam. LC-MS retention time 2.92min; m/z 703.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

2-((2S,5S)-5-Methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole

TFA (0.500 mL, 6.49 mmol) was added dropwise to a stirred solution oftert-butyl(2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinecarboxylate(228 mg, 0.324 mmol) in DCE (6 mL). During the addition, precipitateformed which hindered the stirring. DCM (˜10 mL) was added and theslurry was stirred while the remaining TFA was added. The reaction wasstirred at rt for 30 min, additional TFA was added (˜0.5 mL) and thereaction was stirred 3 h. The reaction was concentrated to yield a TFAsalt of2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(102 mg, 113 mg, 114 mg) as an orange solid. LC-MS retention time 2.756min; m/z 503.14 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.32 (s, 1H), 8.17 (s, 1H), 8.01 (app t, J=8.2 Hz, 2H), 7.85-7.95(m, 6H), 7.80 (s, 1H), 7.73 (s, 1H), 5.02 (app q, J=8.0 Hz, 2H), 3.92(dddd, J=8.7, 7.0, 6.9, 4.8 Hz, 2H), 2.52-2.67 (m, 4H), 2.38-2.49 (m,2H), 1.95-2.07 (m, 2H), 1.55 (app dd, J=6.7, 4.4 Hz, 6H).

2-Bromo-1-(6-bromonaphthalen-2-yl)ethanone

A solution of bromine (0.682 mL, 13.3 mmol) in DCM (20 mL) was added toa solution of 1-(6-bromonaphthalen-2-yl)ethanone (3.30 g, 13.3 mmol)(>90% purity) in DCM (60 mL) and the reaction was stirred at rtovernight. The reaction mixture was concentrated to yield2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g) as an off whitesolid which was used without further purification. LC-MS retention time2.177 min; m/z 342.92 (MNa+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a PHENOMENEX® Luna 10 u C18 2.0×30 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 1 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where Solvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid andSolvent B was 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (400 MHz, chloroform-d) δ ppm 8.49 (s, 1H), 8.03-8.10 (m, 2H), 7.86(d, J=8.5 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.67 (dd, J=8.8, 2.0 Hz, 1H),4.56 (s, 2H).

(1R,3S,5R)-3-(2-(6-Bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

DIPEA (3.47 mL, 19.88 mmol) was added to a stirred slurry of crude2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g, 13.3 mmol) and(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (3.01 g, 13.25 mmol) in acetonitrile (80 mL) and the reaction wasstirred at rt overnight. The reaction was concentrated to dryness andpurified by BIOTAGE® Horizon (160 g SiO₂, 10-20% EtOAc/hexanes). Thefractions containing the desired product were allowed to stand for 3 d.Some fractions had crashed large crystals (collected 240 mg, puredesired product by ¹H NMR). All fractions containing the desired productwere collected and concentrated to a yellow solidified foam which wasslurried with Et₂O (˜40 mL). The white solid that formed was collectedby filtration and rinsed with Et₂O to yield(1R,3S,5R)-3-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.24 g). LC-MS retentiontime 2.760 min; m/z 472, 474.02 (1:1) (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 5% MeOH/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mM ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (400 mHz, MeOD) d ppm 8.61 (br s, 1H), 8.17(s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.94 (d, J=8.9Hz, 1H), 7.71 (dd, J=8.6, 1.8 Hz, 1H), 5.75-5.66 (m, 1H), 5.61-5.46 (m,1H), 4.34-4.26 (m, 1H), 3.46 (br s, 1H), 2.69-2.59 (m, 1H), 2.55-2.44(m, 1H), 1.73 (br s, 1H), 1.54-1.43 (m, 9H), 0.88 (br s, 1H), 0.59-0.53(m, 1H).

(1R,3S,5R)-tert-Butyl3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

(1R,3S,5R)-3-(2-(6-Bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.46 g, 7.28 mmol) andammonium acetate (11.2 g, 146 mmol) were dissolved into toluene (100 mL)and stirred. Then the reaction was placed into an oil bath which hadbeen preheated to 100° C. and stirred at that temperature for 12 h. Thereaction was allowed to cool to rt, concentrated and partitioned betweenDCM (˜200 mL) and ½ sat. aq. NaHCO₃ (˜150 mL). The organic layer waswashed with brine (˜100 mL), dried (MgSO₄), filtered and concentrated toa solidified tan foam. This material was purified on a BIOTAGE® Horizon(160 g SiO₂, loaded with DCM, 30-50% EtOAc/hexanes) to yield(1R,3S,5R)-tert-butyl3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(3.05 g) as a solidified yellow foam. LC-MS retention time 2.238 min;m/z 452.07, 454.02 (1:1) (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3 u C182.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 1mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where Solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.14 (br.s., 1H), 7.96 (d, J=1.8 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.72 (d, J=9.8Hz, 2H), 7.53 (dd, J=8.8, 2.0 Hz, 1H), 7.38 (s, 1H), 4.91 (dd, J=9.0,5.3 Hz, 1H), 3.25-3.56 (m, 2H), 2.40-2.51 (m, 1H), 1.75-1.85 (m, 1H),1.38 (br. s., 1H), 0.86-0.93 (m, 1H), 0.47-0.55 (m, 1H).

(1R,3S,5R)-tert-Butyl3-(4-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.65 g, 4.40 mmol) and Cu(I)I (168 mg, 0.880 mmol) in triethylamine(3.07 mL, 22.0 mmol) and DMF (40 mL) for 20 min. Then,ethynyltrimethylsilane (2.16 g, 22.0 mmol) and Pd(PPh₃)₄ (254 mg, 0.220mmol) were added, the reaction was flushed with nitrogen, sealed andstirred at rt for 24 h. The reaction was concentrated to a brown oil,and purified by BIOTAGE® Horizon (160 g SiO₂, 20-40% EtOAc/hexanes) toyield (1R,3S,5R)-tert-butyl3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(980 mg) as a yellow solid. LC-MS retention time 3.230 min; m/z 346.17(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, chloroform-d) δ ppm 7.18 (s, 1H), 4.77 (dd, J=9.2, 5.1 Hz, 1H),3.20 (br. s., 1H), 3.14-3.39 (m, 1H), 2.33 (dd, J=13.2, 9.4 Hz, 1H),1.69-1.78 (m, 1H), 1.34-1.56 (m, 1H), 1.49 (s, 9H), 0.85 (dt, J=8.5, 5.7Hz, 1H), 0.41-0.47 (m, 1H), 0.22-0.24 (m, 9H).

(1R,3S,5R)-tert-Butyl3-(4-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Potassium carbonate (194 mg, 1.40 mmol) was added to a solution of(1R,3S,5R)-tert-butyl3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(970 mg, 2.81 mmol) in MeOH (30 mL) and the reaction was stirred undernitrogen and then heated at 50° C. (bath temp) for 4 h. The reaction wasconcentrated to ˜5 mL of volume, diluted with DCM (˜40 mL) and washedwith ½ sat brine (˜20 mL). The organics were dried (MgSO₄) filtered andconcentrated to a tan solid. This material was purified by BIOTAGE®Horizon (40 g SiO₂, loaded with DCM, 35-45% EtOAc/hexanes) to yield(1R,3S,5R)-tert-butyl3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(747 mg) as a light yellow solid. LC-MS retention time 2.866 min; m/z272.12 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 7.18 (br. s., 1H), 4.59 (br. s., 1H), 3.36-3.64 (m, 2H), 2.46 (dd,J=13.2, 8.9 Hz, 1H), 2.18-2.31 (m, 1H), 1.64-1.74 (m, 1H), 1.18-1.45 (m,9H), 0.83 (dt, J=8.5, 5.8 Hz, 1H), 0.56 (br. s., 1H).

tert-Butyl(1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(400 mg, 0.880 mmol), (1R,3S,5R)-tert-butyl3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(313 mg, 1.14 mmol) and Cu(I)I (8.4 mg, 0.044 mmol) in triethylamine(0.37 mL, 2.6 mmol) and DMF (8 mL) for 10 min. Then Pd(PPh₃)4 (50.9 mg,0.044 mmol) was added, nitrogen was bubbled through the reaction mixturefor 1 min, and then the flask was sealed and heated at 50° C. for 16 h.The reaction was concentrated to under high vacuum) and the residualsolids were triturated with EtOAc (˜5 mL) and collected by filtration(rinsing with EtOAc and hexanes) to yield tert-butyl(1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(595 mg) as a light yellow solid. The material was used without furtherpurification. LC-MS retention time 3.140 min; m/z 647.35 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

4M HCl (1.546 mL, 6.18 mmol) in dioxane was added to a solution oftert-butyl(1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(200 mg, 0.309 mmol) in dioxane (3 mL) and the reaction was vigorouslystirred for 4 h. The reaction slurry was concentrated to yield an HClsalt of(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(177 mg) as a yellow solid. LC-MS retention time 3.403 min; m/z 893.29(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)d ppm 8.42 (s, 1H), 8.16 (s, 2H), 8.05 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8Hz, 1H), 7.97 (dd, J=8.8, 1.8 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=8.5,1.5 Hz, 1H), 5.01 (dd, J=10.8, 7.8 Hz, 1H), 4.78 (dd, J=10.8, 8.3 Hz,1H), 3.57-3.77 (m, 2H), 3.50-3.56 (m, 1H), 2.61-2.92 (m, 4H), 2.13-2.21(m, 1H), 2.06-2.13 (m, 1H), 1.25 (ddd, J=7.8, 5.0, 2.5 Hz, 1H),0.99-1.14 (m, 2H).

(1R,3S,5R)-Benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Nitrogen was bubbled through a biphasic solution of (1R,3S,5R)-benzyl3-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(prepared in an analogous manner to Intermediate 26) (2.0 g, 4.12 mmol),(1R,3S,5R)-tert-butyl3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.872 g, 4.12 mmol) and Na₂CO₃ (2.184 g, 20.60 mmol) in a mixture ofEtOH (16.0 mL), toluene (16.0 mL) and water (16.0 mL) for 15 min. Then,Pd(PPh₃)₄ (0.143 g, 0.124 mmol) was added, the reaction was flushed withnitrogen, sealed and then heated at 95° C. for 10 h. The crude slurrywas diluted with water (˜20 mL) and extracted with EtOAc (˜100 mL). Theorganic layer was washed with brine, dried (MgSO₄), filtered andconcentrated to a yellow foam. This material was dissolved into aminimal amount of DCM, and purified on a BIOTAGE® Horizon (110 g ofSiO₂, 70-85% EtOAc/hexanes) to yield (1R,3S,5R)-benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.257 g) as a light yellow solidified foam. LC-MS retention time 4.158min; m/z 733.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 1 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.17 (br. s., 1H), 8.07 (s, 1H), 7.86-7.94 (m, 2H), 7.71-7.86 (m,6H), 7.44 (s, 1H), 7.32 (s, 1H), 7.20 (br. s., 5H), 5.14 (d, J=12.3 Hz,1H), 4.91-5.05 (m, 1H), 4.63-4.77 (m, 1H), 3.55-3.69 (m, 2H), 3.29-3.34(m, 1H), 2.46-2.59 (m, 2H), 2.29-2.44 (m, 2H), 1.66-1.80 (m, 2H), 1.30(br. s., 9H), 0.80-0.93 (m, 2H), 0.61 (br. s., 2H).

(1R,3S,5R)-tert-Butyl3-(5-(6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A reaction mixture of (1R,5R)-benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(0.305 g, 0.416 mmol) and NaHCO₂ (0.070 g, 0.832 mmol) in MeOH (15 mL)was charged with 10% Pd/C (0.022 g, 0.021 mmol). The resultingsuspension was vacuum flushed with N₂ (3×) and placed under 1 atm of H₂(balloon) for 3 h at room temperature. The mixture was then filteredthough a pad of diatomaceous earth (CELITE®) and concentrated undervacuum. An off-white solid corresponding to (1R,3S,5R)-tert-butyl3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(0.235 g) was recovered and used without further purification. LC-MS[M+H]⁺=599; Rt=1.96 min is product. Column Luna 3 u C18 2×50 mm; start %B: 0, final % B: 100 Solvent A: 10% Acetonitrile/90% H₂O+1% TFA; SolventB: 90% Acetonitrile/10% H₂O+1% TFA; flow rate 4 ml/min. Run time: 5 min.Purity=94%. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.00 (2H, br. s.),8.11-8.32 (3H, m), 7.88-8.02 (5H, m), 7.72-7.88 (9H, m), 7.63 (4H, br.s.), 4.64 (2H, br. s.), 4.42 (1H, t, J=7.93 Hz), 3.97-4.18 (1H, m), 3.45(1H, br. s.), 3.17 (3H, s), 2.96 (1H, dd, J=13.43, 6.71 Hz), 2.08-2.43(6H, m), 1.66 (2H, br. s.), 1.07-1.50 (20H, m), 0.81-0.89 (3H, m), 0.77(1H, br. s.), 0.45-0.61 (3H, m), 0.30 (1H, br. s.).

(1R,3S,5R)-tert-Butyl3-(5-(6-(4-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

HATU (0.164 g, 0.432 mmol) was added to a solution of(1R,3S,5R)-tert-butyl3-(5-(6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(0.235 g, 0.392 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (0.069 g, 0.39 mmol) and DIEA (0.137 mL, 0.785 mmol) in DMF (10 mL)and the resulting yellow solution was stirred at rt overnight. Thesolvent was removed under reduced pressure and the residue was dissolvedinto methanol, filtered and purified by preparative HPLC (Solvent A: 10%MeOH/90% water/0.1% TFA; Solvent B: 90% MeOH/10% water/0.1% TFA; Column:Sunfire Prep MS C18 30×100 mm 5 u; Wavelength: 220 nM; Flow rate: 30ml/min; Gradient: 0% B to 100% B over 30 min. with a 2 min hold time) toyield a TFA salt of (1R,3S,5R)-tert-butyl3-(5-(6-(4-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(0.10 g) as a white solid. LC-MS [M+H]⁺=756; Rt=2.14 min is product.Column Luna 3 u C18 2×50 mm; start % B: 0, final % B: 100 Solvent A: 10%Acetonitrile/90% H₂O+1% TFA; Solvent B: 90% Acetonitrile/10% H₂O+1% TFA;flow rate 4 ml/min. Run time: 5 min. Purity=96%. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 14.60 (1H, br. s.), 8.39 (3H, d, J=4.88 Hz), 8.09-8.24(4H, m), 7.99-8.08 (6H, m), 7.89-7.98 (5H, m), 7.27 (1H, d, J=8.55 Hz),4.98-5.07 (1H, m), 4.84 (1H, br. s.), 4.42 (1H, t, J=7.32 Hz), 3.74 (1H,br. s.), 3.55 (4H, s), 2.55 (2H, d, J=9.77 Hz), 2.32-2.44 (3H, m), 2.13(1H, dq, J=13.43, 6.71 Hz), 1.94 (1H, dt, J=13.28, 6.79 Hz), 1.75 (1H,dt, J=12.89, 6.22 Hz), 1.40 (4H, d, J=10.07 Hz), 1.11-1.30 (10H, m),0.90-1.00 (5H, m), 0.73-0.88 (10H, m).

Methyl(S)-1-((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

4N HCl in dioxane (2 mL, 8.00 mmol) was added to a stirred solution of aTFA salt of (1R,3S,5R)-tert-butyl3-(5-(6-(4-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(0.10 g, 0.12 mmol) in CH₂Cl₂ (20 mL) and the resulting yellowsuspension was stirred at rt for 2 h. The reaction was concentratedunder vacuum and the resulting residue was triturated with Et₂O to yieldan HCl salt of methyl(S)-1-((1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamateHCl (47 mg) as a yellow solid. LC-MS [M+H]⁺=656; Rt=1.73 min is product.Column Luna 3 u C18 2×50 mm; start % B: 0, final % B: 100 Solvent A: 10%Acetonitrile/90% H₂O+1% TFA; Solvent B: 90% Acetonitrile/10% H₂O+1% TFA;flow rate 4 ml/min. Run time: 5 min. Purity=95%. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 14.47-15.18 (2H, m), 9.77-10.61 (2H, m), 8.30-8.42 (2H,m), 8.17 (1H, s), 7.93-8.10 (10H, m), 7.27 (1H, d, J=8.55 Hz), 5.08 (1H,t, J=7.93 Hz), 4.71 (1H, t, J=8.39 Hz), 4.40-4.46 (1H, m), 3.77 (1H, br.s.), 3.52-3.58 (3H, m), 3.38-3.44 (1H, m), 2.52-2.61 (3H, m), 2.39 (1H,dt, J=13.58, 6.64 Hz), 2.14-2.21 (1H, m), 1.94 (2H, dd, J=8.24, 4.88Hz), 1.15 (1H, d, J=5.80 Hz), 0.93 (4H, d, J=6.71 Hz), 0.75-0.89 (6H,m).

(1R,3S,5R)-Benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A solution of 4.0 M HCl (1.167 mL, 4.67 mmol) in dioxane was added to astirred solution of (1R,3S,5R)-benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(228 mg, 0.311 mmol) in dioxane (3 mL) and the reaction was stirredvigorously at rt for 3 h. The reaction was concentrated to yield an HClsalt of (1R,3S,5R)-benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(233 mg) as a yellow solid. LC-MS retention time 3.988 min; m/z 633.18(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.44 (s, 1H), 8.28 (s, 1H), 8.08-8.18 (m, 3H), 7.92-8.02 (m, 4H),7.84 (br. s., 3H), 7.31 (br. s., 5H), 5.21 (d, J=12.1, 1H), 4.95-5.05(m, 2H), 4.80-4.91 (m, 1H), 3.70-3.77 (m, 1H), 3.59-3.67 (m, 1H),2.77-2.93 (m, 2H), 2.74 (dd, J=13.4, 9.2 Hz, 1H), 2.46 (dt, J=13.5, 6.7Hz, 1H), 2.12-2.22 (m, 1H), 1.83-1.96 (m, 1H), 1.27-1.35 (m, 1H), 1.09(q, J=7.9 Hz, 1H), 0.95 (ddd, J=8.7, 5.9, 5.8 Hz, 1H), 0.75-0.83 (m,1H).

(1R,3S,5R)-Benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

HATU (203 mg, 0.533 mmol) was added to a stirred solution of(1R,5R)-benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(225 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (93 mg,0.53 mmol) in DMF (3 mL) and DIPEA (0.37 mL, 2.1 mmol) and the reactionwas stirred at rt for 3 hr. The crude reaction was concentrated under astream of nitrogen and the residue was dissolved into MeOH and purifiedby preparative HPLC (MeOH/water with an ammonium acetate buffer) toyield (1R,5R)-benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(200 mg) as a yellow solid. LC-MS retention time 4.053 min; m/z 790.25(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.28 (s, 2H), 8.13 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H),7.94-8.02 (m, 4H), 7.76-7.92 (m, 3H), 7.85 (dd, J=8.7, 1.6 Hz, 1H), 7.29(br. s., 5H), 5.21 (d, J=12.1 Hz 1H), 5.16 (dd, J=9.2, 6.9 Hz, 1H), 4.97(t, J=8.2 Hz, 1H), 4.57 (d, J=6.5 Hz, 1H), 3.78-3.87 (m, 1H), 3.68 (s,3H), 3.64-3.77 (m, 2H), 2.66-2.77 (m, 2H), 2.40-2.56 (m, 2H), 2.14-2.25(m, 1H), 2.05-2.14 (m, 1H), 1.87 (d, J=6.5 Hz, 1H), 1.06-1.16 (m, 1H),1.02 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H), 0.87-0.99 (m, 2H),0.74-0.82 (m, 1H).

Methyl(S)-1-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

10% Palladium on carbon (100 mg, 0.094 mmol) was added to a solution of(1R,5R)-benzyl3-(5-(4-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(190 mg, 0.241 mmol) and Na₂CO₃ (50 mg, 0.472 mmol) in THF (10 mL) andthe reaction mixture was vacuum flushed with nitrogen (3×) and then withhydrogen (5×). The reaction mixture was allowed to stir under a balloonof hydrogen for 2 h, filtered through diatomaceous earth (CELITE®) andconcentrated. The residue was resubmitted to the reaction conditions (50mg of 10% Pd/C used) overnight at rt before being filtered throughdiatomaceous earth (CELITE®) and concentrated. The residue was dissolvedinto DMSO/MeOH, filtered and purified by preparative HPLC (MeOH/H₂Ow/0.1% TFA) to yield a TFA salt of methyl(2S)-1-((1R,3S,5R)-3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(55 mg). LC-MS retention time 2.147 min; m/z 656.21 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.28 (s, 1H),8.24 (s, 1H), 8.12 (d, J=8.9 Hz, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.91-8.01(m, 4H), 7.83-7.90 (m, 3H), 7.66 (s, 1H), 5.17 (dd, J=9.2, 7.0 Hz, 1H),4.67 (dd, J=10.7, 7.6 Hz, 1H), 4.58 (d, J=6.7 Hz, 1H), 3.82-3.87 (m,1H), 3.69 (s, 3H), 3.44-3.49 (m, 1H), 2.59-2.77 (m, 3H), 2.48-2.56 (m,1H), 2.16-2.25 (m, 1H), 2.03-2.15 (m, 2H), 1.21 (ddd, J=7.5, 4.9, 2.6Hz, 1H), 1.09-1.15 (m, 1H), 1.04 (d, J=6.7 Hz, 3H), 0.98-1.03 (m, 1H),0.95 (d, J=6.7 Hz, 3H), 0.89-0.95 (m, 1H).

(1R,1′R,3S,3′S,5R,5′R)-tert-Butyl3,3′-(4,4′-(2,2′-binaphthyl-6,6′-diyl)bis(1H-imidazole-4,2-diyl))bis(2-azabicyclo[3.1.0]hexane-2-carboxylate)

Nitrogen was bubbled a solution of (1R,3S,5R)-tert-butyl3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(250 mg, 0.550 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (69.9 mg,0.275 mmol), 1,1′-bis-(diphenylphosphino)-ferrocene (15.42 mg, 0.028mmol) and K₂CO₃ (228 mg, 1.651 mmol) in DMSO (12 mL) for 10 min. Then1,1′-Bis-(diphenylphosphino)-ferrocene) palladium dichloride (22.63 mg,0.028 mmol) was added to the reaction mixture and the nitrogen bubblingwas continued for 10 min before the reaction was sealed and then heatedat 110° C. for 20 h. The reaction was partitioned between water (60 mL)and DCM (60 mL) and the organics were separated, dried (MgSO₄), filteredand concentrated. The crude residue was purified by BIOTAGE® Horizon (40g SiO₂, 70-100% EtOAc/hexanes) to yield(1R,1′R,3S,3′S,5R,5′R)-tert-butyl3,3′-(4,4′-(2,2′-binaphthyl-6,6′-diyl)bis(1H-imidazole-4,2-diyl))bis(2-azabicyclo[3.1.0]hexane-2-carboxylate)(67 mg) as a yellow solid. LC-MS retention time 4.348 min; m/z 749.29(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.22 (s, 4H), 7.91-8.02 (m, 6H), 7.87 (d, J=8.5 Hz, 2H), 7.48 (br.s., 2H), 4.68-4.77 (m, 2H), 3.61 (br. s., 2H), 2.56 (dd, J=13.1, 8.8 Hz,2H), 2.33-2.43 (m, 2H), 1.70-1.79 (m, 2H), 1.31 (br. s., 18H), 0.87 (dt,J=8.5, 5.8 Hz, 2H), 0.63 (br. s., 2H).

6,6′-Bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)-2,2′-binaphthyl

4.0M HCl (1.0 mL, 4.00 mmol) in dioxane was added to a stirred solutionof (1R,1′R,3S,3′S,5R,5′R)-tert-butyl3,3′-(4,4′-(2,2′-binaphthyl-6,6′-diyl)bis(1H-imidazole-4,2-diyl))bis(2-azabicyclo[3.1.0]hexane-2-carboxylate)(62 mg, 0.083 mmol) in dioxane (2 mL) and the reaction slurry wasstirred vigorously for 3 h. The slurry was diluted with MeOH andconcentrated to dryness to yield an HCl salt of6,6′-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)-2,2′-binaphthyl(56 mg) as a light yellow solid. LC-MS retention time 3.971 min; m/z547.25 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD)δ ppm 8.44 (s, 2H), 8.38 (s, 2H), 8.12-8.19 (m, 6H), 8.09 (dd, 2H), 7.97(dd, J=8.5, 1.5 Hz, 2H), 4.97 (dd, J=10.5, 8.1 Hz, 2H), 3.62-3.66 (m,2H), 2.79-2.89 (m, 4H), 2.15-2.22 (m, 2H), 1.29-1.34 (m, 2H), 1.11 (q,J=7.9 Hz, 2H).

6-Bromo-2-(1-ethoxyvinyl)quinoline

Dichlorobis(triphenylphosphine)-palladium(II) (0.289 g, 0.412 mmol) wasadded to a solution of 6-bromo-2-chloroquinoline (1.0 g, 4.1 mmol) andtributyl(1-ethoxyvinyl)stannane (1.79 g, 4.95 mmol) in dioxane (8 mL)and the mixture was stirred at 100° C. for 5 h, desired product wasidentified by LC-MS. The crude reaction mixture was concentrated andpurified by flash silica gel chromatography (eluted with 1:1hexanes/DCM) to yield product 6-bromo-2-(1-ethoxyvinyl)quinoline (720mg) as white solid. LC-MS retention time 4.091 min; m/z 279.84 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode.

2-Bromo-1-(6-bromoquinolin-2-yl)ethanone

NBS (407 mg, 2.287 mmol) was added to a solution of6-bromo-2-(1-ethoxyvinyl)quinoline (530 mg, 1.91 mmol) in THF (10 mL)and water (2.5 mL) and the mixture was stirred at rt for 2 h. Thereaction mixture was partitioned between EtOAc and brine and the organiclayer was concentrated. The crude material was purified by flash silicagel chromatography (eluted with Et₂O/hexanes, gradient from 0 to 5%Et₂O) to yield 2-bromo-1-(6-bromoquinolin-2-yl)ethanone (380 mg) aswhite solid. LC-MS retention time 3.988 min; m/z 329.84 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

(1R,3S,5R)-3-(2-(6-Bromoquinolin-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

DIPEA (0.21 mL, 1.2 mmol) was added to a solution of2-bromo-1-(6-bromoquinolin-2-yl)ethanone (268 mg, 0.815 mmol)) and(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (204 mg, 0.896 mmol) in acetonitrile (8 mL) and the reactionmixture was stirred at rt for 16 h. The reaction mixture was dilutedwith sat. aq. NaHCO₃ (5 mL) and extracted with EtOAc (2×20 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand concentrated. The crude product was purified by flash silica gelchromatography (used DCM as loading solvent, eluted with Et₂O/hexanes,gradient from 10% to 30% Et₂O) to yield(1R,3S,5R)-3-(2-(6-bromoquinolin-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (332 mg) as white solid.LC-MS retention time 4.283 min; m/z 476.88 (MH+). LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX®Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1min, and an analysis time of 5 min where Solvent A was 10% MeOH/90%H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode.

tert-Butyl(1R,3S,5R)-3-(4-(6-bromo-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Ammonium acetate (990 mg, 12.8 mmol) was added to a solution of(1R,3S,5R)-3-(2-(6-bromoquinolin-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (407 mg, 0.856 mmol) intoluene (10 mL) and the mixture was stirred at 120° C. for 3 h. Thereaction mixture was diluted with sat. aq NaHCO₃ (10 mL) and extractedwith EtOAc (50 mL). The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated. The crude material was purified byflash silica gel chromatography (eluted with 1:1 EtOAc/hexanes) to yieldtert-butyl(1R,3S,5R)-3-(4-(6-bromo-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(272 mg) as light yellow solid. LC-MS retention time 3.306 min; m/z456.99 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, chloroform-d) δ ppm 8.08 (d, J=8.5 Hz, 1H), 7.95 (d, J=2.2 Hz, 1H),7.78 (dd, J=8.9, 2.2 Hz, 1H), 7.73-8.14 (m, 3H), 4.86-4.98 (m, 1H),3.70-3.82 (m, 0.5H), 3.26-3.39 (m, 1H), 2.46 (dd, J=13.3, 9.3 Hz, 1H),1.84-1.91 (m, 0.5H), 1.74-1.84 (m, 1H), 1.52 (s, 9H), 0.87-0.97 (m, 1H),0.48-0.61 (m, 1H).

tert-Butyl(1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Pd(OAc)₂ (7.40 mg, 0.033 mmol) was added to a solution of tert-butyl(1R,3S,5R)-3-(4-(6-bromo-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(150 mg, 0.329 mmol), (1R,3S,5R)-tert-butyl3-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(149 mg, 0.329 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (27.0 mg, 0.066mmol) and K₂CO₃ (137 mg, 0.988 mmol) in THF (2 mL) and water (0.50 mL)and the reaction mixture was stirred at 110° C. for 2 h. The reactionmixture was diluted with MeOH, filtered and purified by preparative HPLC(H₂O-MeOH with 10 mM NH₄OAc buffer) to yield tert-butyl(1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(140 mg) as bright yellow solid. LC-MS retention time 3.150 min; m/z700.36 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

2-(2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)quinoline

A solution of 4M HCl (1 mL, 4.00 mmol) in dioxane was added to asuspension of tert-butyl(1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(130 mg, 0.186 mmol) in dioxane (3 mL), MeOH (0.5 mL) and DCM (3 mL) andthe mixture was stirred at rt for 2 h. The reaction was concentrated toyield an HCl salt of2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)quinoline(140 mg) as yellow solid. LC-MS retention time 2.063 min; m/z 500.37(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 9.09 (d, J=9.0 Hz, 1H), 8.66 (s, 1H), 8.56-8.62 (m,2H), 8.47-8.53 (m, 2H), 8.07 (s, 1H), 8.02-8.06 (m, 4H), 4.97 (dd,J=10.8, 8.0 Hz, 1H), 3.65-3.71 (m, 1H), 3.55-3.65 (m, 2H), 2.73-2.86 (m,3H), 2.61-2.72 (m, 1H), 2.07-2.20 (m, 2H), 1.25-1.35 (m, 2H), 1.07 (t,2H).

1-(4-(5-Acetylnaphthalen-1-yl)phenyl)ethanone

A solution of sodium carbonate (2.55 g, 24.09 mmol) in water (20 mL) wasadded to a solution of 1-(5-bromonaphthalen-1-yl)ethanone (1.2 g, 4.8mmol) and 4-acetylphenylboronic acid (1.03 g, 6.26 mmol) in toluene (20mL) and ethanol (20 mL) and then heterogeneous solution was vigorouslystirred with bubbling nitrogen for 15 min. Then Pd(PPh₃)₄ (0.111 g,0.096 mmol) was added and the reaction vessel was sealed and heated atreflux for 6 h. The reaction was cooled and concentrated to dryness. Thecrude residue was taken into EtOAc (˜150 mL) and water (˜100 mL). Thelayers were separated and the organic layer was washed with brine, dried(MgSO₄), filtered and concentrated to an orange solid. The orange solidwas purified on a BIOTAGE® Horizon (40 g SiO₂, DCM) to yield1-(4-(5-acetylnaphthalen-1-yl)phenyl)ethanone (1.31 g) as an off-whitesolid. LC-MS retention time 3.736 min; m/z 289.19 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.75 (d, J=8.8 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99(d, J=8.5 Hz, 1H), 7.94 (dd, J=7.2, 1.1 Hz, 1H), 7.67 (dd, J=8.5, 7.0Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.45-7.51 (m, 2H), 2.79 (s, 3H), 2.70(s, 3H).

2-Bromo-1-(4-(5-(2-bromoacetyl)naphthalen-1-yl)phenyl)ethanone

A solution of bromine (0.47 mL, 9.1 mmol) in DCM (10 mL) was added to asolution of 1-(4-(5-acetylnaphthalen-1-yl)phenyl)ethanone (1.285 g, 4.46mmol) in DCM (20 mL) and the reaction was stirred at rt for 1 d. Thereaction was concentrated to a viscous light orange oil (˜1.92 g). By ¹HNMR the major product appears to be the desired product with peakscorresponding to the two mono brominated regioisomers (˜10%). Thematerial was used without purification. ¹H NMR (400 MHz, chloroform-d) δppm 8.64 (d, J=8.5 Hz, 1H), 8.13-8.17 (m, 2H), 8.05 (d, J=8.5 Hz, 1H),7.94 (dd, J=7.2, 1.1 Hz, 1H), 7.71 (dd, J=8.8, 7.0 Hz, 1H), 7.60-7.64(m, 2H), 7.48-7.55 (m, 2H), 4.60 (s, 2H), 4.53 (s, 2H).

(1R,3S,5R)-3-(2-(4-(5-(2-((1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carbonyloxy)acetyl)naphthalen-1-yl)phenyl)-2-oxoethyl)2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

DIPEA (2.337 mL, 13.38 mmol) was added to a solution of crude2-bromo-1-(4-(5-(2-bromoacetyl)naphthalen-1-yl)phenyl)ethanone (1.99 g,4.46 mmol) and(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (2.03 g, 8.92 mmol) in acetonitrile (50 mL) and the clear yellowsolution was stirred at rt overnight. The reaction was concentrated to ayellow solidified foam which was purified on a BIOTAGE® Horizon (SiO₂,EtOAc/hexanes) to yield(1R,3S,5R)-3-(2-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carbonyloxy)acetyl)naphthalen-1-yl)phenyl)-2-oxoethyl)2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.95 g) as awhite fluffy solid. LC-MS retention time 4.363 min; m/z 737.38 (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.57 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.0 Hz, 2H), 7.99-8.06 (m, 2H),7.68 (dd, J=8.8, 7.0 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.52-7.60 (m, 2H),5.60-5.70 (m, 1H), 5.32-5.56 (m, 3H), 4.24-4.34 (m, 2H), 3.38-3.49 (m,2H), 2.59-2.69 (m, 1H), 2.38-2.55 (m, 3H), 1.61-1.77 (m, 2H), 1.47 (br.s., 18H), 0.81-0.94 (m, 2H), 0.50-0.58 (m, 2H).

(1R,3S,5R)-tert-Butyl3-(5-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A solution of(1R,3S,5R)-3-(2-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carbonyloxy)acetyl)naphthalen-1-yl)phenyl)-2-oxoethyl)2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.01 g, 2.72mmol) and ammonium acetate (4.19 g, 54.4 mmol) in toluene (40 mL) wasstirred and heated at 100° C. overnight. The reaction was concentratedto dryness and the brown solids were partitioned between DCM (150 mL)and ½ sat. aq. NaHCO₃ (100 mL). The organics were dried (MgSO₄),filtered and concentrated. The crude material was not easily purified byflash column chromatography so all fractions containing the desiredproduct or starting material were collected, concentrated andresubmitted to the reaction conditions (now 110° C. overnight). Thereaction was concentrated and the brown solids were partitioned betweenDCM (150 mL) and ½ sat NaHCO₃ (100 mL). The organics were dried (MgSO₄),filtered and concentrated. Approximately ˜30-35% of the material waspurified by preparative HPLC (dissolved into MeOH, filtered, 80-100%MeOH/water, ammonium acetate buffer) to yield (1R,3S,5R)-tert-butyl3-(5-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(148 mg) as a yellow solid. The remaining material was purified bypreparative HPLC (dissolved into MeOH, filtered, 60-100% MeOH/water, TFAbuffer) to yield a TFA salt (1R,3S,5R)-tert-butyl3-(5-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(299 mg). LC-MS retention time 3.100 min; m/z 699.56 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.29 (d, J=8.5 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.3 Hz,2H), 7.59 (dd, J=7.0, 1.0 Hz, 1H), 7.53 (dd, J=8.5, 7.0 Hz, 1H),7.43-7.50 (m, 4H), 7.42 (s, 1H), 7.23 (s, 1H), 4.66-4.80 (m, 2H), 3.60(br. s., 2H), 2.56 (dt, J=13.1, 8.9 Hz, 2H), 2.32-2.46 (m, 2H),1.70-1.78 (m, 2H), 1.38 (br. s., 18H), 0.82-0.90 (m, 2H), 0.63 (br. s.,2H).

(1R,3S,5R)-3-(5-(4-(5-(2-((1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

4M HCl (0.757 mL, 3.03 mmol) in dioxane was added to a solution of(1R,3S,5R)-tert-butyl3-(5-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(141 mg, 0.202 mmol) in dioxane (3.0 mL) and the reaction was stirred atrt for 6 h. The solids were washed down the sides of the vial with MeOHand the reaction was concentrated under a stream nitrogen to yield anHCl salt of(1R,3S,5R)-3-(5-(4-(5-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(119 mg) as a yellow solid. LC-MS retention time 2.333 min; m/z 499.57(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.15 (d, J=8.3 Hz, 1H), 8.03-8.08 (m, 2H), 8.01 (d,J=8.0 Hz, 2H), 7.95 (s, 1H), 7.77 (d, J=6.5 Hz, 1H), 7.68-7.74 (m, 1H),7.65 (d, J=8.0 Hz, 2H), 7.57-7.64 (m, 2H), 5.03 (t, J=9.4 Hz, 1H), 4.97(dd, J=10.8, 8.0 Hz, 1H), 3.57-3.66 (m, 2H), 2.76-2.89 (m, 4H),2.11-2.21 (m, 2H), 1.27-1.34 (m, J=7.7, 5.1, 5.1, 2.6 Hz, 2H), 1.05-1.14(m, 2H).

(2S,3aS,6aS)-2-(2-(4-(6-(2-((2S,3aS,6aS)-1-(tert-Butoxycarbonyl)-octahydrocyclopenta[b]pyrrole-2-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)1-tert-butylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

Neat DIPEA (0.068 mL, 0.388 mmol) was added to a stirred suspension of2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (79 mg,0.176 mmol) and(2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylicacid (90 mg, 0.353 mmol) in an. acetonitrile (1.5 mL) and chloroform(1.5 mL) and the mixture was stirred at r.t. overnight. Reaction mixturewas evaporated to dryness and then purified by silica gel FCC (3% MeOHin DCM) to afford the Intermediate 145 as a tan solid. LC-MS retentiontime: 2.480 min; m/z 793.7 (M−H)⁻.

(2S,3aS,6aS)-tert-Butyl2-(4-(4-(6-(2-((2S,3aS,6aS)-1-(tert-butoxycarbonyl)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate

A stirred suspension of(2S,3aS,6aS)-2-(2-(4-(6-(2-((2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)1-tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (140mg, 0.176 mmol) and ammonium acetate (272 mg, 3.52 mmol) in xylene (4mL) was heated at 140° C. for 2 h. Reaction mixture was cooled to r.t.and diluted with EtOAc (20 ml) and washed with satd. NaHCO₃, water,brine and dried (Na₂SO₄) to afford a brown solid which was purified bysilica gel FCC (3-5% MeOH in DCM) to afford the (2S,3aS,6aS)-tert-butyl2-(4-(4-(6-(2-((2S,3aS,6aS)-1-(tert-butoxycarbonyl)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate.LC-MS retention time: 2.577 min; m/z 755.7 (M+H)⁺.

(2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-Octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)octahydrocyclopenta[b]pyrrole

4N HCl in dioxane (20 equiv) was added to a solution of(2S,3aS,6aS)-tert-butyl2-(4-(4-(6-(2-((2S,3aS,6aS)-1-(tert-butoxycarbonyl)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylatein an. DCM and the mixture was stirred at rt for 2-3 h Anhydrous toluenewas added to the resultant yellow suspension and then evaporated todryness to an HCl salt of(2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)octahydrocyclopenta[b]pyrroleas a beige solid: LC-MS retention time: 2.343 min; m/z 555 (M+H)⁺.

(1R,3S,5R)-3-(4-(6-Bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

TFA (1.028 mL, 13.34 mmol) was added to a solution of(1R,3S,5R)-tert-butyl3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 120) (606 mg, 1.334 mmol) in DCE (20 mL) and reaction wasstirred at rt for 2 h. Then additional TFA (1 mL) was added and thereaction was stirred at rt for 4 h. The reaction was concentrated todryness and the crude brown oil was dissolved into diethyl ether andconcentrated under vacuum (2×) to yield a TFA salt of(1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(786 mg) as a yellow solid. The material was used without furtherpurification. LC-MS retention time 2.558 min; m/z 352.03, 354.05 (1:1)(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 10.55 (br. s., 1H), 8.02 (s, 1H), 7.93 (d, J=1.5 Hz,1H), 7.72 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.8 Hz. 1H), 7.59 (dd, J=8.8,2.0 Hz, 1H), 7.52 (dd, J=8.7, 1.6 Hz, 1H), 7.44 (s, 1H), 5.10 (dd,J=11.8, 7.3 Hz, 1H), 3.49-3.54 (m, 1H), 2.94 (td, J=12.7, 4.6 Hz, 1H),2.68 (dd, J=13.2, 7.2 Hz, 1H), 2.06-2.14 (m, 1H), 1.20-1.26 (m, 1H),1.00-1.09 (m, 1H).

Methyl(S)-1-((1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HATU (411 mg, 1.082 mmol) was added to a solution of a TFA salt of(1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(525 mg, 0.902 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (190 mg, 1.08 mmol) in DMF (10 mL) and DIPEA (0.79 mL, 4.5 mmol)and the reaction was stirred at rt for 4 h. The reaction was dilutedwith EtOAc (˜80 mL) and washed with sat. aq. NaHCO₃, water (30 mL) andbrine (30 mL). The organics were then dried (MgSO₄), filtered andconcentrated to a brown oil (625 mg). This material was purified on aBIOTAGE® Horizon (40 g SiO₂, 40-80% EtOAc/hexanes) to yield methyl(S)-1-((1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(412 mg) as a yellow glass. LC-MS retention time 1.843 min; m/z 511.24,513.12 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 1.0 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

(1R,3S,5R)-tert-Butyl3-(4-((6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Nitrogen was bubbled through a mixture of (1R,3S,5R)-tert-butyl3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 122) (118 mg, 0.432 mmol), methyl(S)-1-((1R,3S,5R)-3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(170 mg, 0.332 mmol) and CuI (3.17 mg, 0.017 mmol) in DMF (4 mL) and TEA(0.14 mL, 0.10 mmol) for 15 min. Then Pd(PPh₃)₄(19.2 mg, 0.017 mmol) wasadded and the reaction vessel was sealed and heated at 60° C. overnight.The reaction was cooled and then additional CuI (5 mg) and TEA (100 μL)were added to the reaction and nitrogen was bubbled through the reactionfor 15 min. Then additional Pd(PPh₃)₄ (12 mg) was added and the reactionwas sealed and stirred at 70° C. for 24 h. The reaction was concentratedunder high vacuum and the residue was partitioned between DCM (25 mL)and water (25 mL). The aqueous was extracted with DCM (2×10 mL) and thecombined organics were washed with brine (˜20 mL), dried (MgSO₄),filtered and concentrated to a viscous dark oil. The material wasdissolved into MeOH, filtered and purified by preparative HPLC(MeOH/water, ammonium acetate buffer) to yield (1R,3S,5R)-tert-butyl3-(4-((6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(187.4 mg) as a yellow solid. The material was used without furtherpurification. LC-MS retention time 1.720 min; m/z 704.59 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 1.0 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

(2S,5S)-2-(2-(6-Bromonaphthalen-2-yl)-2-oxoethyl) 1-tert-butyl5-methylpyrrolidine-1,2-dicarboxylate

DIPEA (0.823 mL, 4.71 mmol) was added to a stirred slurry of2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (Intermediate 118) (1.03 g,3.14 mmol) and(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(0.720 g, 3.14 mmol) in acetonitrile (50 mL) and the reaction wasstirred at rt overnight. The reaction was concentrated to dryness andpurified by BIOTAGE® Horizon (40 g SiO₂, 10-20% EtOAc/hexanes) to yield(2S,5S)-2-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 1-tert-butyl5-methylpyrrolidine-1,2-dicarboxylate (1.09 g) as a yellow solidifiedfoam. LC-MS retention time 4.413 min; m/z 476, 478.20 (1:1) (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.57 (br. s., 1H), 8.14 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H),7.96 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.68 (dd, J=8.8, 1.8 Hz,1H), 5.62-5.70 (m, 1H), 5.47-5.60 (m, 1H), 4.46 (t, J=7.3 Hz, 1H),3.92-4.06 (m, 1H), 2.26-2.37 (m, 2H), 2.05-2.19 (m, 1H), 1.67-1.82 (m,1H), 1.46 (d, J=6.8 Hz, 9H), 1.30 (d, J=6.5 Hz, 3H).

(2S,5S)-tert-Butyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

Ammonium acetate (3.79 g, 49.1 mmol) was added to a solution of(2S,5S)-2-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 1-tert-butyl5-methylpyrrolidine-1,2-dicarboxylate (1.17 g, 2.47 mmol) in toluene (30mL) and the reaction was placed into an oil bath which had beenpreheated to 100° C. and stirred at that temperature overnight. Thereaction was allowed to cool to rt, concentrated and partitioned betweenDCM (100 mL) and ½ sat. aq. NaHCO₃ (75 mL). The organics layer waswashed with brine (˜50 mL), dried (MgSO₄), filtered and concentrated toa solidified tan foam. This material was purified on a BIOTAGE® Horizon(160 g SiO₂, loaded with DCM, 20-35% EtOAc/hexanes) to yield(2S,5S)-tert-butyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(893 mg) as a solidified tan foam. LC-MS retention time 3.410 min; m/z456, 458.22 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 3 min, a hold time of 1 min, and an analysis time of4 min where Solvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid andSolvent B was 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (400 MHz, MeOD) δ ppm 8.19 (br. s., 1H), 8.01 (s, 1H), 7.83-7.93 (m,1H), 7.76-7.83 (m, 2H), 7.55 (dd, J=8.7, 1.6 Hz, 1H), 7.47 (br. s., 1H),4.94 (br. s., 1H), 3.99-4.09 (m, 1H), 2.22-2.36 (m, 2H), 2.09-2.21 (m,1H), 1.72 (br. s., 1H), 1.42 (d, J=6.0 Hz, 3H), 1.34 (br. s., 9H).

(1R,3S,5R)-tert-Butyl3-(4-((6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Nitrogen was bubbled through a solution of (2S,5S)-tert-butyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(127 mg, 0.277 mmol), (1R,3S,5R)-tert-butyl3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(91 mg, 0.33 mmol) and CuI (2.6 mg, 0.014 mmol) in DMF (3 mL) and TEA(0.12 mL, 0.83 mmol) for 15 min. Then Pd(PPh₃)₄(16 mg, 0.014 mmol) wasadded and the reaction vessel was flushed with nitrogen, sealed andheated at 50° C. overnight. The reaction was cooled to rt, nitrogen wasbubbled through the reaction mixture for 20 min., and then additionalCuI (˜4 mg) and Pd(PPh₃)₄ (15 mg) were added. The reaction was flushedwith nitrogen for 5 min., sealed and heated at 60° C. for 1 d. Thereaction was cooled to rt, diluted with methanol, filtered and purifiedby preparative HPLC (MeOH/water with TFA buffer) to yield a TFA salt of(1R,3S,5R)-tert-butyl3-(5-((6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(56.7 mg) as a yellow solid. LC-MS retention time 3.161 min; m/z 649.62(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.31 (s, 1H), 8.21 (s, 1H), 8.07 (d, J=8.8 Hz, 1H),7.99-8.04 (m, 2H), 7.91 (dd, J=8.8, 1.8 Hz, 1H), 7.77-7.87 (m, 1H), 7.69(dd, J=8.7, 1.4 Hz, 1H), 5.13 (t, J=7.5 Hz, 1H), 4.12 (br. s., 1H), 3.61(br. s., 1H), 2.66 (br. s., 1H), 2.45-2.54 (m, 1H), 2.33-2.42 (m, 1H),2.22-2.32 (m, 2H), 1.75-1.86 (m, 2H), 1.25-1.59 (m, 21H), 1.06 (none,1H), 0.90 (dt, J=8.5, 5.8 Hz, 1H), 0.71 (br. s., 1H).

(1R,3S,5R)-3-(4-((6-(2-((2S,5S)-5-Methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

4M HCl (0.611 mL, 2.445 mmol) in dioxane was added to a mixture of a TFAsalt of (1R,3S,5R)-tert-butyl3-(5-((6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(53.6 mg, 0.061 mmol) in dioxane (1.5 mL) and the reaction wasvigorously stirred for 2 h. The reaction was concentrated under a steamof nitrogen overnight to yield an HCl salt of(1R,3S,5R)-3-(4-((6-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(37 mg) which was used without further purification. LC-MS retentiontime 2.302 min; m/z 449.40 (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3 u C182.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where Solvent A was 10% MeOH/90% H₂O/0.1%trifluoroacetic acid and Solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode.

(1R,3S,5R)-3-(44(Trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

TFA (500 μl, 6.49 mmol) was added to a solution of (1R,3S,5R)-tert-butyl3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(299 mg, 0.865 mmol) in DCE (5 mL) and the reaction was stirred at rtfor 30 min. The reaction was concentrated to dryness and thenresubmitted to the reaction conditions for 5 h. The reaction wasconcentrated to yield a TFA salt of(1R,3S,5R)-3-(4-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexaneas a viscous brown oil which was used without further purification.LC-MS retention time 2.755 min; m/z 246.25 (MH+). LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX®Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1min, and an analysis time of 5 min where Solvent A was 10% MeOH/90%H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode.

Methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(4-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate

HATU (428 mg, 1.125 mmol) was added to a stirred solution of(1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(212 mg, 0.865 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (197 mg, 1.125 mmol) in DMF (3 mL) and DIPEA (1.2 mL, 6.9 mmol) andthe reaction was stirred at rt overnight. The reaction was concentratedto dryness and then purified with a BIOTAGE® Horizon (25 g SiO₂, 40-60%EtOAc/hexanes) to yield methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate(203 mg) as a yellow glass. LC-MS retention time 3.095 min; m/z 403.29(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 7.17 (br. s., 1H), 5.04-5.11 (m, 1H), 4.54 (d, J=6.8Hz, 1H), 3.65 (s, 3H), 3.54-3.61 (m, 1H), 2.82 (s, 1H), 2.39-2.50 (m,1H), 2.27-2.36 (m, 1H), 2.04-2.15 (m, 1H), 1.94-2.04 (m, 1H), 1.11 (dt,J=8.7, 5.6 Hz, 1H), 0.95 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.8 Hz, 3H),0.73-0.79 (m, 1H), 0.21 (s, 9H).

Methyl(S)-1-((1R,3S,5R)-3-(4-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Potassium carbonate (34.3 mg, 0.248 mmol) was added to a solution ofmethyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate(200 mg, 0.497 mmol) in methanol (5 mL) and the reaction was flushedwith nitrogen, sealed and then heated at 50° C. for 4 h. and thenstirred at rt overnight. The reaction was concentrated to dryness andthen purified on a BIOTAGE® Horizon (12 g SiO₂, 70-90% EtOAc/hexanes) toyield methyl(S)-1-((1R,3S,5R)-3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(151 mg) as a yellow glass. LC-MS retention time 1.788 min; m/z 331.32(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

(1R,3S,5R)-tert-Butyl3-(5-(6-((2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A mixture of (1R,3S,5R)-tert-butyl3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(208 mg, 0.457 mmol), methyl(S)-1-((1R,3S,5R)-3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(151 mg, 0.457 mmol) and CuI (8.70 mg, 0.046 mmol) in DMF (4 mL) and TEA(0.19 mL, 1.4 mmol) was vacuum flushed with nitrogen (6×) over 10minutes. Then Pd(PPh₃)₄ (53 mg, 0.046 mmol) was added and the reactionmixture was vacuum flushed with nitrogen (3×), sealed and heated at 60°C. for 20 h. The reaction was concentrated under a steam of nitrogenovernight and then purified preparative HPLC (40-80% MeOH/water with aTFA buffer) to yield a TFA salt of (1R,3S,5R)-tert-butyl3-(5-(6-((2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(270 mg) as a yellow solid. LC-MS retention time 2.995 min; m/z 704.70(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.28 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=8.8 Hz, 1H),7.98-8.03 (m, 2H), 7.89 (dd, J=8.5, 1.8 Hz, 1H), 7.69-7.85 (m, 1H), 7.67(dd, J=8.7, 1.4 Hz, 1H), 5.11 (br. s., 1H), 4.84-4.91 (m, 2H), 4.55 (d,J=5.8 Hz, 1H), 3.70-3.77 (m, 1H), 3.67 (s, 3H), 2.72 (dd, J=13.6, 9.0Hz, 1H), 2.55-2.63 (m, 1H), 2.39-2.50 (m, 2H), 2.11-2.20 (m, 1H),2.02-2.11 (m, 1H), 1.81-1.89 (m, 1H), 1.45 (br. s., 9H), 1.07-1.14 (m,1H), 1.00 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 0.84-0.93 (m, 2H),0.74 (br. s., 1H).

1-(6-Bromoquinolin-2-yl)ethanone

3M HCl (aq.) (10 mL, 30.0 mmol) was added to a suspension of6-bromo-2-(1-ethoxyvinyl)quinoline (780 mg, 2.80 mmol) in acetone (20mL) and the reaction mixture was stirred at rt for 5 h. The reactionmixture was concentrated, dissolved into THF (20 mL) and treated with 3NHCl (aq.) (5 mL) was clear reaction solution was stirred at 60° C. for 5h. The reaction was, cooled, neutralized with aq. NaOH and NaHCO₃ andextracted with EtOAc. The organic layer was dried, and concentrated toyield crude 1-(6-bromoquinolin-2-yl)ethanone (710 mg) as white solid.LC-MS retention time 3.703 min; m/z 250, 251.99 (1:1) (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

1-(6-(4-Acetylphenyl)quinolin-2-yl)ethanone

Pd(OAc)₂ (62.9 mg, 0.280 mmol) was added to a solution of4-acetylphenylboronic acid (689 mg, 4.20 mmol),1-(6-bromoquinolin-2-yl)ethanone (700 mg, 2.8 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (230 mg, 0.560 mmol)and K₂CO₃ (1.16 g, 8.40 mmol) in dioxane (10 mL) and water (2.500 mL)and the reaction mixture was refluxed at 110° C. for 5 h. The reactionmixture was cooled to rt and partitioned between sat.aq NH₄Cl and EtOAc.The organic layer was washed with NaHCO₃ and brine and then dried(MgSO₄), filtered, concentrated and purified by flash silica gelchromatography (loading solvent: DCM, eluted with 0˜20% EtOAc/hexanes)to yield 1-(6-(4-acetylphenyl)quinolin-2-yl)ethanone (781 mg) as whitesolid. LC-MS retention time 3.776 min; m/z 290.29 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.35 (d, J=8.3 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.19(d, J=8.5 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.08-8.16 (m, 3H), 7.85 (d,J=8.3 Hz, 1H), 7.82-7.89 (m, 1H), 2.91 (s, 3H), 2.69 (s, 3H).

2-Bromo-1-(6-(4-(2-bromoacetyl)phenyl)quinolin-2-yl)ethanone

Pyridinium tribromide (221 mg, 0.691 mmol) was added to a suspension of1-(6-(4-acetylphenyl)quinolin-2-yl)ethanone (100 mg, 0.346 mmol) and HBr(0.061 mL, 0.35 mmol) in acetic acid (3 mL) the reaction mixture wasstirred at 70° C.) for 6 h. The reaction was concentrated under vacuumand the residue was partitioned between aq NaHCO₃ (15 mL) and EtOAc (30mL+10 mL+10 mL). The organic layers were combined, washed with brine,dried, filtered and concentrated to yield crude2-bromo-1-(6-(4-(2-bromoacetyl)phenyl)quinolin-2-yl)ethanone (120 mg) aswhite solid. LC-MS retention time 4.138 min; m/z 448.01 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

(2S,4S)-2-(2-(6-(4-(2-((2S,4S)-1-(tert-Butoxycarbonyl)-4-methylpyrrolidine-2-carbonyloxy)acetyl)phenyl)quinolin-2-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate

DIPEA (0.094 mL, 0.537 mmol) was added to a solution of2-bromo-1-(6-(4-(2-bromoacetyl)phenyl)quinolin-2-yl)ethanone (60 mg,0.134 mmol) and(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(64.6 mg, 0.282 mmol) in acetonitrile (2 mL) and the mixture was stirredat rt for 16 h. The reaction mixture was partitioned between EtOAc (20mL+20 mL)/aq NaHCO₃ (5 mL). The combined organic layers were washed withaq NaHCO₃, brine, dried, filtered and concentrated to yield crude(2S,4S)-2-(2-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carbonyloxy)acetyl)phenyl)quinolin-2-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (100 mg) as orangesolid. This material was used without further purification. LC-MSretention time 4.558 min; m/z 742.36 (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% SolventA/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 5% MeOH/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mM ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode.

(2S,4S)-tert-Butyl2-(5-(4-(2-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)quinolin-6-yl)phenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

Ammonium acetate (207 mg, 2.69 mmol) was added to a solution of(2S,4S)-2-(2-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carbonyloxy)acetyl)phenyl)quinolin-2-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (100 mg, 0.134 mmol)in toluene (3 mL) and the reaction mixture was stirred at 120° C.(microwave reactor) for 3 h. The reaction was partitioned between EtOAc(20 mL+10 mL+10 mL) and aq NaHCO₃ (10 mL) and the combined organiclayers were dried, filtered and concentrated. This crude product waspurified by preparative HPLC (H₂O—CH₃CN with 10 mM NH₄OAc buffer) toyield product (2S,4S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(16.6 mg) as a yellow solid. LC-MS retention time 3.270 min; m/z 704.72(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

2-(2-((2S,4S)-4-Methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline

4M HCl (0.2 mL, 0.800 mmol) in dioxane was added to a solution of(2S,4S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(16.6 mg, 0.024 mmol) in dioxane (1 mL) and the reaction mixture wasstirred at rt for 3 d. The reaction mixture was concentrated to yield acrude HCl salt of2-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline(19.1 mg) as yellow solid. LC-MS retention time 2.765 min; m/z 504.47(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

(2S,5S)-2-(2-(6-(4-(2-((2S,4S)-1-(tert-Butoxycarbonyl)-4-methylpyrrolidine-2-carbonyloxy)acetyl)phenyl)quinolin-2-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate

DIPEA (0.059 mL, 0.335 mmol) was added to a solution of2-bromo-1-(6-(4-(2-bromoacetyl)phenyl)quinolin-2-yl)ethanone (50 mg,0.11 mmol) and(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(54 mg, 0.24 mmol) in acetonitrile (2 mL) and the reaction mixture wasstirred at rt for 16 h. The reaction was partitioned between EtOAc(20+20 mL)/aq NaHCO₃ (5 mL). The combined organic layers were washedwith sat. aq NaHCO₃, brine, dried, filtered and concentrated to yieldcrude(2S,5S)-2-(2-(6-(4-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)phenyl)quinolin-2-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (69 mg) as orangesolid. This crude was used without further purification. LC-MS retentiontime 4.483 min; m/z 744.61 (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3 u C182.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where Solvent A was 10% MeOH/90% H₂O/0.1%trifluoroacetic acid and Solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode.

(2S,5S)-tert-Butyl2-(5-(4-(2-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)quinolin-6-yl)phenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

Ammonium acetate (107 mg, 1.39 mmol) was added to a suspension of(2S,5S)-2-(2-(6-(4-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)phenyl)quinolin-2-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (69 mg, 0.093 mmol)in toluene (Volume: 2 mL) and the reaction mixture was stirred at 120°C. (microwave reactor) for 3 h. The reaction was partitioned betweenEtOAc (10 mL+5 mL+5 mL) and aq NaHCO3 (5 mL). The combined organiclayers were dried, filtered and concentrated and the crude product waspurified by preparative HPLC (H₂O—CH₃CN with 10 mM NH₄OAc buffer) toyield product (2S,5S)-tert-butyl2-(4-(6-(4-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(13.4 mg) as a yellow solid. LC-MS retention time 4.350 min; m/z 702.29(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.37 (d, J=8.8 Hz, 1H), 8.16 (s, 1H), 8.07-8.10 (m, 2H), 8.03 (d,J=8.8 Hz, 1H), 7.79-7.88 (m, 5H), 7.40 (s, 1H), 4.90-5.07 (m, 2H),3.99-4.13 (m, 2H), 2.10-2.39 (m, 6H), 1.68-1.82 (m, 2H), 1.43 (d, J=6.0Hz, 6H), 1.24-1.59 (m, 22H).

2-(2-((2S,5S)-5-Methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-6-(4-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline

4M HCl (0.2 mL, 0.8 mmol) in dioxane was added to a solution of(2S,5S)-tert-butyl2-(5-(6-(4-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(12.7 mg, 0.018 mmol) in dioxane (1 mL) and the mixture was stirred atrt for 3 d. The reaction mixture was concentrated to yield a crude HClsalt of2-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline(18.1 mg) as yellow solid. LC-MS retention time 2.597 min; m/z 504.46(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 9.09 (d, J=9.0 Hz, 1H), 8.66 (s, 1H), 8.54-8.61 (m,2H), 8.51 (d, J=9.0 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.00-8.08 (m, 4H),7.99 (s, 1H), 5.14 (t, J=8.5 Hz, 1H), 5.07 (t, J=8.0 Hz, 1H), 3.90-4.04(m, 2H), 2.52-2.75 (m, 4H), 2.39-2.53 (m, 2H), 1.98-2.14 (m, 2H), 1.59(dd, J=9.7, 6.7 Hz, 6H).

Intermediate 173 was prepared in an analogous manner to Intermediate 139in Scheme 35 by utilizing 6-bromo-2-chloroquinoxaline as the startingmaterial rather than 6-bromo-2-chloroquinoline. Analytical data shownbelow.

6-Bromo-2-(1-ethoxyvinyl)quinoxaline

The reaction yielded the desired product (380 mg) as a white solid.LC-MS retention time 4.178 min; m/z 278.9, 280.98 (1:1) (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

2-Bromo-1-(6-bromoquinoxalin-2-yl)ethanone

The reaction yielded the desired product (390 mg) as a white solid.LC-MS retention time 3.743 min; m/z 331.12 (1:2:1) (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

(1R,3S,5R)-3-(2-(6-Bromo quinoxalin-2-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

The reaction yielded the desired product (270 mg) as a pink/orangesolid. LC-MS retention time 4.115 min; m/z 473, 475.81 (1:1) (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 0.8 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

tert-Butyl(1R,3S,5R)-3-(4-(6-bromo-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

The reaction yielded the desired product (125 mg) as a red/orange solid.LC-MS retention time 3.958 min; m/z 453.90, 455.87 (1:1) (MH−). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (400 MHz, MeOD) δ ppm 9.40 (br. s.,1H), 8.22 (d, J=2.0 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.93-7.99 (m, 1H),7.90 (dd, J=8.8, 2.0 Hz, 1H), 4.71-4.81 (m, 1H), 3.59 (br. s., 1H),2.49-2.63 (m, 1H), 2.31-2.45 (m, 1H), 1.68-1.82 (m, 1H), 1.16-1.53 (m,5H), 0.81-0.94 (m, 1H), 0.64 (br. s., 1H).

tert-Butyl(1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

The reaction yielded the desired product (64.4 mg) as a bright yellowsolid. LC-MS retention time 3.696 min; m/z 699.3 (MH−). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.45 (s,1H), 8.31 (s, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.97(s, 1H), 7.81-7.95 (m, 4H), 7.60 (s, 1H), 4.57-4.80 (m, 2H), 3.23-3.60(m, 2H), 2.23-2.48 (m, 4H), 1.61-1.75 (m, 2H), 1.28 (br. s., 18H),0.73-0.87 (m, 2H), 0.59 (br. s., 2H).

Methyl((1S)-1-(((2S,4S)-2-(4-(6-(4-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

The reaction yielded an HCl salt of the desired product (80 mg) as ayellow solid. LC-MS retention time 2.915 min; m/z 501.42 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 9.54 (s, 1H), 8.40-8.43 (m, 1H), 8.34 (s, 1H), 8.23-8.30 (m, 2H),8.13 (s, 1H), 8.00-8.08 (m, 4H), 4.88-5.08 (m, 2H), 3.53-3.77 (m, 2H),2.64-2.90 (m, 4H), 2.08-2.22 (m, 2H), 1.23-1.36 (m, 2H), 1.02-1.14 (m,2H).

(1R,3S,5R)-tert-Butyl3-(4-((6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Compound was prepared in an analogous manner to Intermediate 153 withthe appropriate starting materials to yield a TFA salt of the titlecompound (121 mg) as a yellow glass. LC-MS retention time 4.100 min; m/z647.37 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

(1R,3S,5R)-3-(4-((6-(2-((2S,4S)-4-Methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

2M HCl (0.33 mL, 0.66 mmol) in dioxane was added to a solution of a TFAsalt of (1R,3S,5R)-tert-butyl3-(5-((6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(115 mg, 0.131 mmol) in dioxane (2 mL) and the reaction was stirredvigorously overnight. The reaction was concentrated to yield an HCl saltof(1R,3S,5R)-3-(4-((6-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(87 mg) which was used without further purification. LC-MS retentiontime 2.793 min; m/z 449.41 (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3 u C182.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where Solvent A was 10% MeOH/90% H₂O/0.1%trifluoroacetic acid and Solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode.

Intermediate 178 was prepared in an analogous manner to the preparationof Intermediate 117 in Scheme 29 utilizing(S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid as a startingmaterial rather than(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid.Analytical data for the intermediates shown below.

(S)-2-(4-(6-(2-((S)-2-(tert-Butoxycarbonylamino)-3-methylbutanoyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)-3-methylbutanoate

The reaction yielded the desired product (700 mg) as a tan solid. LC-MSretention time 2.243 min; m/z 717.5 (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of1.0 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% SolventA/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where Solvent A was 5% MeOH/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mM ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode.

tert-Butyl((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamate

The reaction yielded the desired product (453 mg) as a yellow solid.LC-MS retention time 2.407 min; m/z 677.6 (MH−). LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna3 u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of1.0 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% SolventA/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where Solvent A was 5% MeOH/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mM ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode.

(S)-1-(5-(4-(6-(2-((S)-1-Amino-2-methylpropyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-methylpropan-1-amine

The reaction yielded an HCl salt of the desired product (390 mg) as ayellow solid. LC-MS retention time 2.080 min; m/z 477.4 (MH−). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 1.0 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode.

Intermediate 181 was prepared in an analogous manner to the preparationof Intermediate 117 in Scheme 29 utilizing(S)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid as a startingmaterial rather than(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid.Analytical data for the intermediates shown below.

(S)-3-(2-(4-(6-(2-((S)-4-(tert-Butoxycarbonyl)morpholine-3-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)4-tert-butyl morpholine-3,4-dicarboxylate

The reaction yielded an HCl salt of the desired product (1.60 g) as anoff-white solid foam. LC-MS retention time 4.413 min; m/z 770.29 (MNa+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.47 (s, 1H), 8.13 (s, 1H), 7.98-8.11 (m, 5H), 7.86(d, J=8.3 Hz, 3H), 5.39-5.70 (m, 4H), 4.66-4.83 (m, 2H), 4.46-4.63 (m,2H), 3.91-4.03 (m, 2H), 3.68-3.85 (m, 4H), 3.49-3.59 (m, 3H), 3.27-3.40(m, 1H), 1.51 (s, 18H).

(R)-tert-Butyl3-(5-(4-(6-(2-((R)-4-(tert-butoxycarbonyl)morpholin-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)morpholine-4-carboxylate

The reaction yielded the desired product (1.12 g) as an orange solid.LC-MS retention time 3.608 min; m/z 707.94 (MH+). LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX®Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1min, and an analysis time of 5 min where Solvent A was 10% MeOH/90%H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (400 MHz, MeOD) δ ppm 8.22 (br. s.,1H), 8.09 (s, 1H), 7.90-7.97 (m, 2H), 7.75-7.89 (m, 6H), 7.49 (br. s.,1H), 7.41 (br. s., 1H), 5.17-5.24 (m, 2H), 4.42 (t, J=11.2 Hz, 2H),3.82-3.95 (m, 6H), 3.59 (tt, J=11.6, 3.0 Hz, 2H), 3.39-3.51 (m, 2H),1.50 (d, J=2.8 Hz, 18H).

(R)-3-(5-(4-(6-(2-((R)-Morpholin-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)morpholine

The reaction yielded an HCl salt of the desired product (312 mg) as ayellow solid. LC-MS retention time 2.988 min; m/z 507.72 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Intermediate 184 was prepared in an analogous manner to the preparationof Intermediate 117 in Scheme 29 utilizing(S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid as a startingmaterial rather than(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid.Analytical data for the intermediates shown below.

(S)-2-(2-(4-(6-(2-((S)-1-(tert-Butoxycarbonyl)piperidine-2-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)1-tert-butyl piperidine-1,2-dicarboxylate

The reaction yielded the desired product (1.67 g) as a solidified lightyellow foam. LC-MS retention time 4.850 min; m/z 766.37 (MNa+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.47 (s, 1H), 8.13 (s, 1H), 7.99-8.10 (m, 5H),7.83-7.89 (m, 3H), 5.32-5.67 (m, 4H), 4.92-5.13 (m, 2H), 3.93-4.11 (m,2H), 3.00-3.28 (m, 2H), 2.40 (br. s., 2H), 1.68-1.84 (m, 6H), 1.49 (s,18H), 1.39-1.67 (m, 4H)

(S)-tert-Butyl2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)piperidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

The reaction yielded the desired product (1.18 g) as a bright yellowsolid. LC-MS retention time 3.778 min; m/z 703.97 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.22 (br. s., 1H), 8.09 (s, 1H), 7.93 (t, J=7.7 Hz, 2H), 7.73-7.88(m, 6H), 7.46 (br. s., 1H), 7.38 (br. s., 1H), 5.47 (br. s., 2H),4.03-4.15 (m, 2H), 2.99-3.12 (m, 2H), 2.46 (br. s., 2H), 1.80-1.94 (m,2H), 1.50 (d, J=2.3 Hz, 18H), 1.44-1.76 (m, 8H).

(S)-2-(5-(4-(6-(2-((S)-Piperidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)piperidine

The reaction yielded an HCl salt of the desired product (280 mg) as ayellow solid. LC-MS retention time 3.015 min; m/z 503.69 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.06 (br. s., 2H), 9.85 (br. s., 2H), 8.48 (s, 1H), 8.36(s, 1H), 8.09-8.19 (m, 3H), 7.96-8.09 (m, 7H), 4.70 (br. s., 2H),3.42-3.53 (m, 2H), 3.14 (br. s., 2H), 2.10-2.37 (m, 4H), 1.60-2.00 (m,8H).

Intermediate 187 was prepared in an analogous manner to the preparationof Intermediate 117 in Scheme 29 utilizing(2S,5R)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(prepared according to JOC 1995, p. 5011) as a starting material ratherthan (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylicacid. Analytical data for the intermediates shown below.

(2S,5R)-2-(2-(4-(6-(2-((2S,5R)-1-(tert-Butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate

The reaction yielded the desired product (979 mg). LC-MS retention time4.796 min; m/z 766.19 (MNa+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min, and an analysis time of5 min where Solvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid andSolvent B was 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (400 MHz, chloroform-d) δ ppm 8.47 (br. s., 1H), 8.13 (d, J=2.5 Hz,1H), 7.99-8.11 (m, 5H), 7.86 (dd, J=7.8, 2.3 Hz, 3H), 5.21-5.77 (m, 4H),4.51-4.58 (m, 1H), 4.47 (dd, J=7.8, 4.5 Hz, 1H), 4.17-4.26 (m, 1H),4.07-4.14 (m, 1H), 2.23-2.48 (m, 6H), 1.60-1.68 (m, 2H), 1.44-1.52 (m,18H), 1.25 (d, J=6.3 Hz, 3H), 1.21 (d, J=6.3 Hz, 3H).

(2S,5R)-tert-Butyl2-(5-(4-(6-(2-((2S,5R)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

The reaction yielded the desired product (561 mg) as an orange solidfoam. LC-MS retention time 3.673 min; m/z 703.95 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

2-((2S,5R)-5-Methylpyrrolidin-2-yl)-5-(4-(6-(2-((2S,5R)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazole

The reaction yielded an HCl salt of the desired product (157 mg) as alight orange solid. LC-MS retention time 2.975 min; m/z 503.71 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where Solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.84-10.25 (m, 4H), 8.54 (s, 1H), 8.36 (s, 1H), 7.95-8.22(m, 10H), 5.15 (br. s., 2H), 4.00 (br. s., 2H), 2.53-2.63 (m, 4H),2.30-2.41 (m, 2H), 1.67-1.82 (m, 2H), 1.43 (d, J=4.3 Hz, 6H).

Intermediate 189 was prepared as shown in Scheme 49 utilizing(S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid asstarting material. Analytical data for the intermediates shown below.

tert-Butyl(2S)-2-(4-(4-(6-(2-((2S)-1-(tert-butoxycarbonyl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methylene-1-pyrrolidinecarboxylate

Hunig's base (0.43 mL, 2.47 mmol) was added to a stirred solution of(S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid(509 mg, 2.241 mmol) and2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (500 mg,1.121 mmol) in MeCN (25 mL). The mixture was stirred for 18 h at RT. Thesolvent was removed in vacuo and the residue was taken up in ethylacetate and washed with water, saturated sodium bicarbonate solution,and brine. After being concentrated, the residue was taken up in xylene(25 mL) and ammonium acetate (1.3 g, 16.85 mmol) was added. The pressurevessel was sealed and heated at 140° C. for 2.5 h. The reaction mixturewas taken up in ethyl acetate and washed with saturated sodiumbicarbonate solution and brine. After being concentrated, the crudeproduct was charged (methylene chloride) to a 80 g Thompson silica gelcartridge (eluted with 15% B to 100% B over 1 L where Solvent B=ethylacetate and Solvent A=hexanes) to yield tert-butyl(2S)-2-(4-(4-(6-(2-((2S)-1-(tert-butoxycarbonyl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methylene-1-pyrrolidinecarboxylate(380 mg, 45% yield). LC-MS retention time 3.32 min; calcd. forC₄₂H₄₇N₆O₄: 699.36 m/z Found 699.41 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.21 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.97(s, 1H), 7.87-7.83 (m, 6H), 7.54 (s, 1H), 7.46 (s, 1H), 5.14 (s, 2H),5.19 (s, 2H), 4.30 (br s, 2H), 4.15 (br s, 2H), 3.22-3.16 (m, 2H),2.81-2.76 (m, 2H), 1.51/1.31 (s, 18H).

2-((S)-4-Methylenepyrrolidin-2-yl)-4-(4-(6-(2-((S)-4-methylenepyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazole

A solution of 4N HCl in dioxane (10 mL) was added to tert-butyl(2S)-2-(4-(4-(6-(2-((2S)-1-(tert-butoxycarbonyl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methylene-1-pyrrolidinecarboxylate(380 mg. 0.544 mmol) in MeOH (10 mL) and stirred at ambient conditionsfor 4 hours, concentrated, and dried under vacuum. Tetra HCl salt(assume theoretical: 350 mg). LC-MS retention time 2.68 min; calcd. forC₃₂H₃₁N₆: 499.26 m/z Found 499.21 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

Intermediate 191 was prepared as shown in Scheme 50 utilizing(S)-2-(tert-butoxycarbonylamino)propanoic acid as starting material.Analytical data for the intermediates shown below.

tert-Butyl((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)carbamate

Hunig's base (0.39 mL, 2.24 mmol) was added to a stirred solution of(S)-2-(tert-butoxycarbonylamino)propanoic acid (424 mg, 2.24 mmol) and2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (500 mg,1.121 mmol) in MeCN (50 mL). The mixture was stirred for 18 h at RT. Thesolvent was removed in vacuo and the residue was taken up in ethylacetate and washed with water, saturated sodium bicarbonate solution,and brine. After being concentrated, the residue was taken up in xylene(25 mL) and ammonium acetate (1.5 g, 20.18 mmol) was added. The pressurevessel was sealed and heated at 140° C. for 3.5 h. The reaction mixturewas taken up in ethyl acetate and washed with saturated sodiumbicarbonate solution and brine. After being concentrated, the crudeproduct was charged (methylene chloride) to a 90 g Thompson silica gelcartridge (eluted with 15% B to 100% B over 1 L where Solvent B=ethylacetate and Solvent A=hexanes) to provide tert-Butyl((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)carbamate(368 mg, 47% yield). NOTE: Sample was only partially soluble inmethylene chloride. LC-MS retention time 3.24 min; calcd. forC₃₆H₄₃N₆O₄: 623.33 m/z. Found 623.37 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.20 (s, 1H), 8.11 (s, 1H), 7.95 (t, J=8.24Hz, 2H), 7.86-7.79 (m, 6H), 7.46 (s, 1H), 7.37 (s, 1H), 4.93-4.89 (m,2H), 1.57-1.48 (m, 24H).

(S)-1-(4-(4-(6-(2-((S)-1-Aminoethyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)ethanamine

A solution of 4N HCl in dioxane (10 mL) was added to tert-butyl((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)carbamate(368 mg. 0.59 mmol) in MeOH (10 mL) and stirred at ambient conditionsfor 5 hours, concentrated, and dried under vacuum. Tetra HCl salt(assume theoretical: 334 mg). LC-MS retention time 1.33 min; calcd. forC₂₆H₂₇N₆: 423.23 m/z Found 423.17 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 1mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 2 min, a hold time of 1 min and ananalysis time of 3 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

Intermediate 193 was prepared as shown in Scheme 51 utilizing(S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid as startingmaterial. Analytical data for the intermediates shown below.

tert-Butyl((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)(methyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)methylcarbamate

Hunig's base (0.78 mL, 4.48 mmol) was added to a stirred solution of(S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (456 mg, 2.241mmol) and 2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone(500 mg, 1.121 mmol) in MeCN (50 mL). The mixture was stirred for 18 hat RT. The solvent was removed in vacuo and the residue was taken up inethyl acetate and washed with water, saturated sodium bicarbonatesolution, and brine. After being concentrated, the residue was taken upin xylene (25 mL) and ammonium acetate (859 mg, 11.15 mmol) was added.The pressure vessel was sealed and heated at 140° C. for 3 h. Thereaction mixture was taken up in ethyl acetate and washed with saturatedsodium bicarbonate solution and brine. After being concentrated, thecrude product was charged (methylene chloride) to a 90 g Thompson silicagel cartridge (eluted with 15% B to 100% B over 1 L where SolventB=ethyl acetate and Solvent A=hexanes) to yield tert-butyl((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)(methyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)methylcarbamate(460 mg, 58% yield). LC-MS retention time 3.28 min; calcd. forC₃₈H₄₇N₆O₄: 651.37 m/z Found 651.34 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.24-8.12 (m, 2H), 7.98-7.82 (m, 8H),7.52-7.42 (m, 2H), 5.47 (br s, 2H), 2.77 (s, 3H), 2.76 (s, 3H), 1.64 (m,6H), 1.52 (s, 18H).

(S)—N-Methyl-1-(4-(4-(6-(2-((S)-1-(methylamino)ethyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)ethanamine

A solution of 4N HCl in dioxane (10 mL) was added to tert-butyl((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)(methyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)methylcarbamate(434 mg. 0.667 mmol) in MeOH (10 mL) and stirred at ambient conditionsfor 3 hours, concentrated and dried under vacuum. Tetra HCl salt (assumetheoretical: 396 mg). LC-MS retention time 1.44 min; calcd. forC₂₈H₃₁N₆: 451.26 m/z Found 451.17 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 1mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 2 min, a hold time of 1 min and ananalysis time of 3 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

Intermediate 196 was prepared as shown in Scheme 52 utilizing(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid asstarting material. Analytical data for the intermediates shown below.

(2S,4S)-1-(tert-Butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid

A solution of(S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (4g, 17.60 mmol) in 2-propanol (10 mL) was added to a nitrogen purgedsuspension of 10% palladium on carbon (936 mg) in 2-propanol (240 mL)and the flask was charged with hydrogen gas (1 atm). After being stirred18, the catalyst was removed by filtration over CELITE® and the filtrateconcentrated. LC analysis showed the sample contained ˜14% of thetrans-isomer, and recrystallization from toluene enriched the cis-isomerto 96% (16:1). LC-MS retention time 3.26 min; calcd. for C₁₁H₂₀N₆O₄:230.14 m/z Found 252.14 [M+Na]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® 2×5 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min and an analysis time of 5 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90%methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm4.21-4.17 (m, 1H), 3.76-3.67 (m, 1H), 2.96-2.92 (m, 1H), 2.49-2.46 (m,1H), 2.30-2.29 (m, 1H), 1.59-1.51 (m, 1H), 1.47/1.43 (m, 9H), 1.10-1.06(m, 3H).

tert-Butyl(2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate

Hunig's base (0.381 mL, 2.181 mmol) was added to a stirred solution of(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(500 mg, 2.18 mmol) and2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (486 mg,1.09 mmol) in acetonitrile (11 mL). The heterogeneous mixture wasstirred for 18 h at RT and additional Hunig's base (1 equiv) was addedand the mixture was stirred for 24 h. The solvent was removed in vacuoand the residue was taken up in methylene chloride and washed withsaturated sodium bicarbonate solution, brine, and dried over sodiumsulfate. Wash was repeated 2×. The crude product, isolated as a tanfoam, was taken up in xylene (15 mL) and ammonia acetate (1.261 g, 16.36mmol) was added. The pressure vessel was sealed and placed into apreheated oil bath (140° C.) and stirred for 2 h. The reaction mixturewas taken up in ethyl acetate and washed with saturated sodiumbicarbonate solution and brine. After being concentrated, the crudeproduct was charged (methylene chloride) to a 80 g Thompson silica gelcartridge (eluted with 25% B to 100% B over 1.5 L and hold 0.5 L B.Solvent B=ethyl acetate and Solvent A=hexanes) to yield tert-butyl(2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate(214.2 mg 27.9%) as a yellow foam. LC-MS retention time 3.32 min; calcd.for C₄₂H₅₁N₆O₄: 703.40 m/z Found 703.28 [M+H]⁺. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.20 (s, 1H), 8.12 (s, 1H), 7.96-7.94 (m, 2H),7.87-7.82 (m, 6H), 7.50 (s, 1H), 7.42 (s, 1H), 4.87 (br. s, 2H), 3.81(br. s, 2H), 3.24-3.18 (m, 2H), 2.53-2.50 (m, 2H), 2.36 (br s, 2H),1.82-1.74 (m, 2H), 1.46/1.23 (s, 18H), 1.17-1.16 (m, 6H).

2-((2S,4S)-4-Methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole

A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl(2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate(200 mg. 0.285 mmol) in MeOH (5 mL) and stirred at ambient conditionsfor 2 hours, concentrated, and dried under vacuum. Tetra HCl salt(assume theoretical: 185 mg). LC-MS retention time 2.64 min; calcd. forC₃₂H₃₅N₆: 503.29 m/z Found 503.20 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

Intermediate 201 was prepared as shown in Scheme 53 utilizing(2S,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid asstarting material. Analytical data for the intermediates shown below.

The trans-isomer was isolated from a mixture of cis, trans, and thedimethyl analog which could be obtained from methyl iodide alkylation of(S)-1-tert-butyl 2-methyl-5-oxopyrrolidine-1,2-dicarboxylate accordingto the procedure described in Tetrahedron Letters, 2003, 3203-3205. ¹HNMR (500 MHz, MeOD) δ ppm 4.66-4.64 (m, 1H), 3.80 (s, 3H), 2.34-2.29 (m,1H), 2.04-1.99 (m, 1H), 1.49 (s, 9H), 1.21-1.19 (m, 3H).

Borane-methyl sulfide complex (17.67 mL, 35.3 mmol) was added to asolution of Intermediate 197 (6.06 g, 23.55 mmol) in THF (180 mL), andthe reaction mixture was heated at 40° C. for 16 hr. The solvent wasremoved in vacuo and the residue was partitioned between EtOAc and water(250 mL each). The aqueous layer was extracted with EtOAc (2×60 mL), andthe combined organic phase was dried with Na₂SO₄, and concentrated invacuo. The resultant colorless oil was purified with a flashchromatography (10-65% EtOAc/Hexane) to afford Intermediate 198 as acolorless oil (3.65 g). ¹H NMR (CDCl₃, δ=7.24 ppm, 400 MHz): 4.36-4.33(dd, J=2.4, 10, 0.4H), 4.26-4.23 (dd, J=3, 8.9, 0.6H), 3.73-3.63 (‘s’overlapped with ‘m’, 4H), 2.97-2.85 (m, 1H), 2.37 (m, 1H), 2.04 (m, 1H),1.81 (m, 1H), 1.44-1.39 (two ‘s’, 9H), 1.03-1.00 (two ‘s’, 3H).

(2S,4R)-1-(tert-Butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid

To a solution of ester Intermediate 198 (3.63 g, 14.92 mmol) in ethanol(36 mL) was added solution of LiOH (0.393 g, 10.42 mmol) in water (18.00mL), and the reaction mixture was stirred at room temperature for 22 hr.The organic solvent was evaporated in vacuo and the residue was dilutedwith water (30 mL) and washed with ethylacetate (50 mL). It was chilledin ice-water bath, and acidified to a pH range of ˜2 with 1N HCl. It wasthen extracted with EtOAc (50 mL, 2×). The organic layer was dried withNa₂SO₄ and concentrated in vacuo to afford Intermediate 199 as acolorless oil, which became a white solid upon extended exposure to highvacuum (3.3 g). ¹H NMR (CDCl₃, δ=7.24 ppm, 400 MHz): 4.37-4.27(overlapped ‘m’ 1H), 3.72-3.50 (m, 1H), 3.01-2.83 (overlapped ‘m’, 1H),2.50-2.11 (m, 2H), 1.89-1.57 (m, 1H), 1.47-1.39 (two ‘s’, 9H), 1.04-1.03(two ‘s’, 3H).

tert-Butyl(2S,4R)-2-(4-(4-(6-(2-((2S,4R)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate

Hunig's base (0.381 mL, 2.181 mmol) was added to a stirred solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(500 mg, 2.18 mmol) and2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (486 mg,1.09 mmol) in acetonitrile (11 mL). The heterogeneous mixture wasstirred for 18 h at RT and additional Hunig's base (1 eqv) was added andthe mixture was stirred for 24 h. The solvent was removed in vacuo andthe residue was taken up in methylene chloride and washed with saturatedsodium bicarbonate solution, brine, and dried over sodium sulfate. Washwas repeated 2×. The crude product, isolated as a tan foam, was taken upin xylene (15 mL) and ammonia acetate (1.261 g, 16.36 mmol) was added.The pressure vessel was sealed and placed into a preheated oil bath(140° C.) and stirred for 2 h. The reaction mixture was taken up inethyl acetate and washed with saturated sodium bicarbonate solution andbrine. After being concentrated, the crude product was charged(methylene chloride) to a 80 g Thompson silica gel cartridge (elutedwith 25% B to 100% B over 1.5 L and hold 0.5 L B. Solvent B=ethylacetate and Solvent A=hexanes) to yield tert-butyl(2S,4R)-2-(4-(4-(6-(2-((2S,4R)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate(214.2 mg 27.9%) as a yellow foam. LC-MS retention time 3.32 min; calcd.for C₄₂H₅₁N₆O₄: 703.40 m/z Found 703.28 [M+H]⁺. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.20 (s, 1H), 8.12 (s, 1H), 7.96-7.94 (m, 2H),7.87-7.82 (m, 6H), 7.50 (s, 1H), 7.42 (s, 1H), 4.87 (br. s, 2H), 3.81(br. s, 2H), 3.24-3.18 (m, 2H), 2.53-2.50 (m, 2H), 2.36 (br s, 2H),1.82-1.74 (m, 2H), 1.46/1.23 (s, 18H), 1.17-1.16 (m, 6H).

2-((2S,4R)-4-Methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4R)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole

A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl(2S,4R)-2-(4-(4-(6-(2-((2S,4R)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate(200 mg. 0.285 mmol) in MeOH (5 mL) and stirred at ambient conditionsfor 2 hours, concentrated, and dried under vacuum. Tetra HCl salt(assume theoretical: 185 mg). LC-MS retention time 2.64 min; calcd. forC₃₂H₃₅N₆: 503.29 m/z Found 503.20 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

Intermediate 203 was prepared as shown in Scheme 54 utilizing asstarting material(1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (which could be prepared according to WO 2004/052850). Analyticaldata for the intermediates shown below.

tert-Butyl(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Hunig's base (0.384 mL, 2.2 mmol) was added to a stirred solution of2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (0.491 g,1.100 mmol) and(1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (500 mg, 1.1 mmol) in acetonitrile (11 mL). The heterogeneousmixture was stirred for 20 h at RT the solvent was removed in vacuo. Theresidue was taken up in ethyl acetate and washed with saturated sodiumbicarbonate solution, brine, and dried over sodium sulfate. Wash wasrepeated 2×. The crude product was taken up in xylene (11 mL) andammonia acetate (1.27 g, 16.5 mmol) was added. The pressure vessel wassealed and placed into a preheated oil bath (140° C.) and stirred for 2h. The solvent was removed in vacuo and the residue was taken up inethyl acetate and washed with saturated sodium bicarbonate solution andbrine. After being concentrated, the crude product was charged(methylene chloride) to a 80 g Thompson silica gel cartridge (elutedwith 25% B to 100% B over 1.5 L and hold 0.5 L B. Solvent B=ethylacetate and Solvent A=hexanes) to yield tert-butyl(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(418.9 mg, 43%) as a light yellow solid. LC-MS retention time 3.46 min;calcd. for C₄₂H₄₇N₆O₄: 699.37 m/z Found 699.33 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 minand an analysis time of 5 min where Solvent A was 5% methanol/95%water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.11 (s, 1H), 7.96-7.93 (m,2H), 7.85-7.80 (m, 6H), 7.45 (br. s, 1H), 7.37 (br. s, 1H), 5.36 (br. s,2H), 3.72 (br. s, 1H), 3.64 (br. s, 1H), 2.82 (br. s, 1H), 2.72 (br s,1H), 2.43 (br. s, 1H), 2.15 (br. s, 1H), 1.70 (br. s, 2H), 1.55/1.33 (s,18H), 1.10 (br. s, 1H), 0.94 (br. s, 1H), 0.88 (br. s, 1H), 0.81 (br. s,1H).

(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-Azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

A solution of 4N HCl in dioxane (10 mL) was added to tert-butyl(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(375 mg. 0.537 mmol) in MeOH (3 mL) and stirred at ambient conditionsfor 2 hours, concentrated, and dried under vacuum. Tetra HCl salt(assume theoretical: 346 mg). LC-MS retention time 2.75 min; calcd. forC₃₂H₃₁N₆: 499.26 m/z Found 499.22 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

Intermediate 209 was prepared as shown in Scheme 55 utilizing asstarting material(1S,3S,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (which could be prepared according to WO 2004/052850). Analyticaldata for the intermediates shown below.

To a solution of the diastereomeric mixture (at the carbon carrying themethyl group) of Intermediate 197 (4.75 g, 18.46 mmol) was addedsuperhydride (19.20 mL, 19.20 mmol) dropwise at −50° C. in a dryice/acetone bath over 10 min. Hunig's base (13.58 mL, 78 mmol) wasadded, stirred for 10 min, DMAP (0.122 g, 0.997 mmol) was added as asolid, stirred for 15 min, and trifluoroacetic anhydride (2.98 mL, 21.08mmol) was added dropwise over 15 mins. The dry ice/acetone bath wasremoved and the reaction mixture was stirred for 4 h while being allowedto warm to room temperature. The reaction mixture was washed with water(50 mL), sat. NaCl (30 mL), and concentrated in vacuo. The resultingcrude material was purified by flash chromatography (8-60% EtOAc/Hexane)to afford ester Intermediate 204 as a yellow oil (2.85 g). ¹H NMR(CDCl₃, 400 MHz): 6.36 (s, 0.5H), 6.25 (s, 0.5H), 4.70-4.57 (m, 1H),3.78 (s, 3H), 2.96 (m, 1H), 2.54 (m, 1H), 1.70 (s, 3H), 1.50 (s, 4.5H),1.44 (s, 4.5H).

Diethylzinc (1.1 M in toluene, 59.1 mL, 65.0 mmol) was added dropwiseover 20 min to a cooled (−23° C.) toluene (60 mL) solution ofIntermediate 203 (5.23 g, 21.68 mmol), and stirred for 10 min.Chloroiodomethane (9.44 mL, 130 mmol) was added dropwise over 10 min,and the reaction mixture was stirred at −21° C. for 16 hr. Sat. NaHCO₃(60 mL) was added to the reaction mixture, the cooling bath was removed,and the mixture was stirred for 10 min. It was then filtered, and thefilter cake was washed with toluene (50 mL). The filterate waspartitioned, and the organic layer was dried with Na₂SO₄, andconcentrated in vacuo. The resulting crude material was purified withflash chromatography (2-10% EtOAc/Hexane) to afford Intermediate 205(first elute; colorless oil; 2.88 g) and Intermediate 206 (second elute;colorless oil; 1.01 g). Relative stereochemical assignment was madebased on NOE studies. Intermediate 205: ¹H NMR (CDCl₃, 400 MHz):4.65-4.52 (m, 1H), 3.72 (s, 3H), 3.28-3.17 (m, 1H), 2.44-2.32 (m, 1H),2.16-2.10 (m, 1H), 1.51-1.42 (two s, 9H), 1.24 (s, 3H), 1.07 (m, 1H),0.69-0.60 (m, 1H).

(1S,3S,5S)-2-(tert-Butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid

To a solution of Intermediate 205 (2.88 g, 11.28 mmol) in ethanol (20mL) was added a solution of LiOH (0.324 g, 13.54 mmol) in water (10.00mL), and the mixture was stirred at room temperature for 6 hr. Most ofthe volatile component was removed in vacuo, and the residue waspartitioned between water (20 mL) and ether (20 mL). The aqueous layerwas chilled in an ice-water bath, acidified with a 1N HCl to a pH regionof 2, and extracted with EtOAc (30 mL, 4×). The combined organic phasewas dried with Na₂SO₄, evaporated in vacuo to give Intermediate 207 as asticky solid (2.55 g). ¹H NMR (CDCl₃, 400 MHz): 4.64 (m, 1H), 3.25 (appts, 1H), 2.70-2.40 (m, 1H), 2.14 (m, 1H), 1.54-1.44 (m, 9H), 1.27 (s,3H), 1.10-0.80 (m, 1H), 0.67 (m, 1H).

tert-Butyl(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

Hunig's base (0.475 mL, 2.72 mmol) was added to a stirred solution of2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (0.607 g,1.36 mmol) and (1S,3S,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (729.0 mg, 2.72 mmol) in dry acetonitrile (12 mL). Theheterogeneous mixture was stirred for 20 h at RT the solvent was removedin vacuo. The residue was taken up in ethyl acetate and washed withsaturated sodium bicarbonate solution, brine, and dried over sodiumsulfate. Wash was repeated 2×. The crude product was taken up in xylene(12 mL) and ammonia acetate (1.57 g, 20.39 mmol) was added. The pressurevessel was sealed and placed into a preheated oil bath (140° C.) andstirred for 2 h. The solvent was removed in vacuo and the residue wastaken up in ethyl acetate and washed with saturated sodium bicarbonatesolution and brine. After being concentrated, the crude product wascharged (methylene chloride) to a 80 g Thompson silica gel cartridge(eluted with 25% B to 100% B over 1.5 L and hold 0.5 L B. SolventB=ethyl acetate and Solvent A=hexanes) to yield tert-butyl(1S,3S,5S)-3-(4-(4-(6-(2-41S,3S,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(279 mg, 27%) as a light yellow solid. LC-MS retention time 3.56 min;calcd. for C₄₄H₅₁N₆O₄: 727.40 m/z Found 727.41 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPHENOMENEX® 2.0×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 minand an analysis time of 5 min where Solvent A was 5% methanol/95%water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.11 (s, 1H), 7.96-7.93 (m,2H), 7.83-7.80 (m, 6H), 7.43 (br. s, 1H), 7.35 (br. s, 1H), 5.35 (br. s,2H), 3.42 (br. s, 1H), 3.36 (br. s, 1H), 2.61 (br. s, 1H), 2.53 (br.s,2H), 2.72 (br s, 1H), 1.55/1.33 (s, 25H), 1.06 (br. s, 1H), 0.85 (br. s,1H), 0.72 (br. s, 1H).

(1S,3S,5S)-5-Methyl-3-(4-(4-(6-(2-41S,3S,5S)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(250 mg. 0.344 mmol) in MeOH (5 mL) and stirred at ambient conditionsfor 2 hours, concentrated, and dried under vacuum. Tetra HCl salt(assume theoretical: 231 mg). LC-MS retention time 3.09 min; calcd. forC₃₄H₃₅N₆: 527.29 m/z Found 527.35 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® 2.0×50mm column using a SPD-10AV UV-Vis detector at a detector wave length of220 nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was95% methanol/5% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Intermediate 212 was prepared as shown in Scheme 56 utilizing(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (which could be prepared according to WO 2004/052850 as startingmaterial. Analytical data for the intermediates shown below.

(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid

Intermediate 210 was prepared from Intermediate 206 as described abovefor Intermediate 207. ¹H NMR (CDCl₃, 400 MHz): 4.13 (app br s, 1H), 3.06(app br s, 1H), 2.55/2.41 (overlapping app br s, 2H), 1.51 (s, 9H), 1.27(s, 3H), 0.76 (app t, J=5.6, 1H), 0.60 (app br s, 1H).

tert-Butyl(1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

Hunig's base (0.29 mL, 1.66 mmol) was added to a stirred solution of2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (0.37 g,0.83 mmol) and(1R,3R,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (0.40 g, 1.66 mmol) in dry acetonitrile (9 mL). The heterogeneousmixture was stirred for 20 h at RT the solvent was removed in vacuo. Theresidue was taken up in ethyl acetate and washed with saturated sodiumbicarbonate solution, brine, and dried over sodium sulfate. Wash wasrepeated 2×. The crude product was taken up in xylene (9 mL) and ammoniaacetate (1.3 g, 16.6 mmol) was added. The pressure vessel was sealed andplaced into a preheated oil bath (140° C.) and stirred for 2 h. Thesolvent was removed in vacuo and the residue was taken up in ethylacetate and washed with saturated sodium bicarbonate solution and brine.After being concentrated, the crude product was charged (methylenechloride) to a 90 g Thompson silica gel cartridge (eluted with 25% B to100% B over 1.5 L and hold 0.5 L B. Solvent B=ethyl acetate and SolventA=hexanes) to yield tert-butyl(1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(80 mg, 10%). LC-MS retention time 3.37 min; calcd. for C₄₄H₅₁N₆O₄:727.40 m/z. Found 727.38 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was95% methanol/5% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD)δ ppm 8.19 (s, 1H), 8.08 (s, 1H), 7.92-7.91 (m, 2H), 7.85-7.77 (m, 6H),7.47 (s, 1H), 7.38 (s, 1H), 4.67 (br. s, 2H), 3.93-3.90 (m, 2H),2.63-2.57 (m, 2H), 2.20-2.14 (m, 2H), 1.31-1.23 (m, 24H), 0.92 (app. d,J=6.7 Hz, 1H), 0.82 (br. s, 1H), 0.77-0.75 (m, 2H).

(1R,3S,5R)-5-Methyl-3-(4-(4-(6-(2-((1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

A solution of 4N HCl in dioxane (5 mL) was added to tert-butyl(1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(48 mg. 0.066 mmol) in MeOH (1 mL) and stirred at ambient conditions for2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assumetheoretical: 44 mg). LC-MS retention time 2.82 min; calcd. for C₃₄H₃₅N₆:527.29 m/z Found 527.26 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was95% methanol/5% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Intermediate 218 was prepared as shown in Scheme 57 utilizing(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(Intermediate 194) as starting material. Analytical data for theintermediates shown below:

(2S,4S)-tert-Butyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

Hunig's base (1.6 mL, 9.0 mmol) was added to a stirred mixture of2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (3.0 g, 9.0 mmol) and(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(2.062 g, 8.99 mmol) in dry acetonitrile (100 mL) and stirred at rt for16 h. Additional(S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (500mg) and Hunig's base (0.4 mL) were added and stirring was continued for15 h. The solvent was removed by rotary evaporation and the residue wastaken up in EtOAc and washed with sat'd NaHCO₃ soln, brine, and dried(Na₂SO₄). The ester was taken up in xylene (100 mL) and treated withNH₄OAc (10.40 g, 135 mmol) in a sealed pressure vessel which wasimmersed in an oil bath at 140° C. and stirred for 2 h. The solvent wasremoved by rotary evaporation under high vacuum and the residue wastaken up in EtOAc and washed with sat'd NaHCO₃ soln, brine, and dried(Na₂SO₄).

This residue was purified with a Thompson 300 g silica gel cartridge(gradient elution 3% B to 100% B over 4.5 L and hold 0.5 L B; SolventB=ethyl acetate and Solvent A=hexanes) to yield (2S,4S)-tert-butyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(2 g) as a foam. For the purpose of characterization, approximately 25mg was dissolved in methanol (2 mL) and subjected to prep HPLC (gradient0-100% B over a 25 min at 40 mL/min) on a PHENOMENEX® Luna column(30×100 mm, 10 u); Solvent B=95% CH₃CN-5% H₂O-10 mM NH₄OAc and A=5%CH₃CN-95% H₂O-10 mM NH₄OAc. LC-MS retention time 2.61 min; calcd. forC₂₃H₂₇BrN₃O₂: 456.13 m/z. found 456.09 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.03 (s, 1H), 7.89 (d, J=8.6 Hz,1H), 7.82 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.57 (d, J=10.4 Hz,1H), 7.51 (s, 1H), 4.91 (br. s, 1H), 3.81 (t, J=8.3 Hz, 1H), 3.21 (t,J=8.3 Hz, 1H), 2.53-2.48 (m, 1H), 2.37-2.34 (m, 1H), 1.81-1.73 (m, 1H),1.46/1.21 (s, 9H), 1.16 (d, J=6.1 Hz, 3H).

(2S,4S)-tert-Butyl2-(4-(6-bromonaphthalen-2-yl)-5-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

NCS (203 mg, 1.52 mmol) was added to a solution of (2S,4S)-tert-butyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(560 mg, 1.39 mmol) in dry DMF (15 mL) and the mixture was heated at 50°C. for 16 h. The solvent was removed by nitrogen purge and the residuewas purified with a Thompson 90 g silica gel cartridge (gradient elution5%-100% B over 2 L; Solvent B=ethyl acetate and Solvent A=hexanes) toyield (2S,4S)-tert-butyl2-(4-(6-bromonaphthalen-2-yl)-5-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(255 mg) as a tan foam. For purpose of characterization, approximately20 mg was dissolved in methanol (2 mL) and subject to prep HPLC(gradient 0-100% B over a 25 min at 40 ml/min) on a PHENOMENEX® Lunacolumn (30×100 mm, 10 u); Solvent B=95% CH₃CN-5% H₂O-10 mM NH₄OAc andA=5% CH₃CN-95% H₂O-10 mM NH₄OAc. LC-MS retention time 2.61 min; calcd.for C₂₃H₂₆BrClN₃O₂: 492.09 m/z. found 492.03 [M+H]. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX®Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% SolventA/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.09 (s, 1H), 7.91 (br. s, 2H),7.83 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 4.79-4.75 (m, 1H), 3.78(t, J=8.9 Hz, 1H), 3.19 (t, J=10.4 Hz, 1H), 2.49 (quin, J=6.1 Hz, 1H),2.36-2.32 (m, 1H), 1.78 (q, J=11.9 Hz, 1H), 1.45/1.24 (s, 9H), 1.15 (d,J=6.1 Hz, 3H).

(2S,4S)-tert-Butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

Hunig's base (2.3 mL, 13.1 mmol) was added to a stirred mixture of2-bromo-1-(4-bromophenyl)ethanone (3.64 g, 13.1 mmol) and(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(3.0 g, 13 mmol) in dry acetonitrile (150 mL) and stirred at rt for 16h. The solvent was removed by rotary evaporation and the residue wastaken up in EtOAc and washed with water, sat'd NaHCO₃ soln, brine, anddried (Na₂SO₄). The resulting ester was taken up in xylene (150 mL) andtreated with NH₄OAc (15.1 g, 196 mmol) in a sealed pressure vessel whichwas immersed in an oil bath at 140° C. and stirred for 2 h. The solventwas removed by rotary evaporation under high vacuum and the residue wastaken up in EtOAc and washed with sat'd NaHCO₃ soln, brine, and dried(Na₂SO₄), filtered and concentrated. The crude product was purified witha Thompson 300 g silica gel cartridge (gradient elution 3% B to 100% Bover 4.5 L and hold 0.5 L B; Solvent B=ethyl acetate and SolventA=hexanes) to yield (2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(3.5 g, 59%) as a foam. For purpose of characterization, approximately25 mg was dissolved in methanol (2 mL) and subject to prep HPLC(gradient 0-100% B over a 25 min at 40 ml/min) on a PHENOMENEX® Lunacolumn (30×100 mm, 10 u); Solvent B=95% CH₃CN-5% H₂O-10 mM NH₄OAc andA=5% CH₃CN-95% H₂O-10 mM NH₄OAc. LC-MS retention time 3.06 min; calcd.for C₁₉H₂₅BrN₃O₂: 408.11 m/z. found 408.16 [M+H]. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX®Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% SolventA/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 7.62 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.6 Hz,2H), 7.38 (s, 1H), 4.84-4.81 (m, 1H), 3.79 (t, J=8.6 Hz, 1H), 3.17 (t,J=10.4 Hz, 1H), 2.50-2.45 (m, 1H), 2.36-2.31 (m, 1H), 1.76-1.69 (m, 1H),1.45/1.20 (s, 9H), 1.14 (d, J=6.1 Hz, 3H).

(2S,4S)-tert-Butyl4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Pd(Ph₃P)₄ (213 mg, 0.185 mmol) was added to a nitrogen purged suspensionof (2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate,(1.5 g, 3.7 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.88 g,7.38 mmol) and potassium acetate (906 mg, 9.23 mmol) in dioxane (35 mL).The pressure reaction vessel was degassed, sealed, and immersed in anoil bath at 85° C. for 16 hours. The mixture was diluted with EtOAc andwashed with sat'd NaHCO₃ soln, brine, and dried (Na₂SO₄), filtered andconcentrated. The crude product was purified with a Thompson 160 gsilica gel cartridge (gradient elution 10% to 100% B over 1 L. SolventB=ethyl acetate and Solvent A=hexanes) to yield (2S,4S)-tert-butyl4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.8 g, 97%) as a foam. LC-MS retention time 1.78 min; calcd. forC₁₉H₂₇BN₃O₄: 372.21 m/z. found 372.18 [M+H]. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

(2S,4S)-tert-Butyl2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-4-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

Pd(Ph₃P)₄ (27.1 mg, 0.023 mmol) was added to a nitrogen purgedsuspension of (2S,4S)-tert-butyl2-(5-(6-bromonaphthalen-2-yl)-4-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate,(230 mg, 0.469 mmol), (2S,4S)-tert-butyl4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(234 mg, 0.515 mmol) and NaHCO₃ (197 mg, 2.34 mmol) in an argon-degassedsolution of DME (4 mL) and water (1 mL). The pressure vessel was chargedwith argon, sealed, and immersed into a pre-heated oil bath (85° C.) andstirred for 14 h. The mixture was diluted with EtOAc (Note: THF and MeOHwere added to aid dissolution) and washed with sat'd NaHCO₃ soln, brine,dried (Na₂SO₄), filtered and concentrated. The residue was purifiedutilizing a Thompson 90 g SiO₂ column (Gradient elution 5% to 100% B for2 L and hold for 0.5 L Solvent B=ethyl acetate and Solvent A=hexanes) toyield (2S,4S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-4-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(270 mg, 70%) as a foam. For the purpose of characterization approx. 20mg was dissolved in MeOH (up to 2 mL) and subject to prep HPLC vial (0to 100% B over a 30 min gradient at 40 ml/min) using a PHENOMENEX® Lunacolumn (30×100 mm, S10) where B=95% CH₃CN-5% H₂O-10 mM NH₄OAc and A=5%CH₃CN-95% H₂O-10 mM NH₄OAc. LC-MS retention time 3.90 min; calcd. forC₄₂H₅₀ClN₆O₄: 737.36 m/z. found 737.43 [M+H]. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (500 MHz, MeOD) δ ppm 8.21 (s, 1H), 8.16 (s, 1H), 8.03 (d, J=8.6 Hz,1H), 7.99 (d, J=8.6 Hz, 2H), 7.91-7.81 (m, 6H), 7.42 (s, 1H), 4.86(under MeOH, 1H), 4.80-4.877 (m, 1H), 3.82-3.77 (m, 2H), 3.20 (t, J=10.4Hz, 2H), 2.52-2.47 (m, 2H), 2.37-2.34 (m, 2H), 1.83-1.73 (m, 2H),1.46/1.26/1.23 (s, 18H), 1.16 (m, 6H).

4-Chloro-2-((2S,4S)-4-methylpyrrolidin-2-yl)-5-(6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazole

4N HCl in dioxane (5 mL) was added to a stirred solution of(2S,4S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-4-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(30 mg, 0.041 mmol) in MeOH (1 mL) and the mixture was stirred at RT for2 h, concentrated, and dried under high vacuum for 2 h. LC-MS retentiontime 3.31 min; calcd. for C₃₂H₃₄ClN₆: 537 26 m/z Found 537.37 [M+H]. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min and an analysis time of 5 min where Solvent A was 5%methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1%TFA. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode.

(S)-Methyl 4,5-dihydro-1H-pyrazole-5-carboxylate

DMAP (2.83 g, 23.2 mmol) was added to a solution of (S)-methyl4,5-dihydro-1H-pyrazole-5-carboxylate (prepared according to J. Am.Chem. Soc., 119:8379-8380 (1997); 2.95 g, 23.02 mmol) and Boc₂O (11.9mL, 51.2 mmol) in CH₂Cl₂ (40 mL) and stirred at ambient condition for22.5 hr. Additional Boc₂O (1.83 g) was added and stirring was continuedfor 15 hr. Silica gel was added to the reaction mixture and the solventwas removed in vacuo, and the resultant mesh was submitted to a BIOTAGE®purification (300 g silica gel; column was eluted with 30-50%EtOAc/hexanes) to afford (S)-methyl4,5-dihydro-1H-pyrazole-5-carboxylate as a yellow oil (3.956 g). Asample of the starting pyrazoline, contaminated with the product, wasalso retrieved (695 mg). ¹H NMR (CDCl₃, δ=7.24 ppm, 400 MHz): 6.80 (s,1H), 4.67 (dd, J=12.6, 6.1 Hz, 1H), 3.75 (s, 3H), 3.22 (ddd, J=18.5,12.6, 1.4 Hz, 1H), 2.94 (ddd, J=18.5, 6.1, 1.7 Hz, 1H), 1.5 (s, 9H).LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₀H₁₆N₂NaO₄: 251.10. found 251.26.

(S)-1-tert-Butyl 5-methyl 1H-pyrazole-1,5(4H,5H)-dicarboxylate

Sodium cyanoborohydride (0.769 g, 12.2 mmol) was added in batches over 1min to an acetic acid (7.0 mL) solution of (S)-methyl4,5-dihydro-1H-pyrazole-5-carboxylate (1.05 g, 4.61 mmol), and stirredat ambient condition for 20 h. Formaldehyde (1 mL of 37% in water) wasadded dropwise over 4 min, and stirring was continued for 4.5 h. Thevolatile component was removed in vacuo and the residue was treated withsaturated NaHCO₃ (10 mL) and CH₂Cl₂ (30 mL), the mixture was shaken andthe phases were separated. The organic layer was washed with anadditional saturated NaHCO₃ solution (10 mL), dried (MgSO₄), filteredand concentrated in vacuo. The resultant crude material was purifiedwith a BIOTAGE® (240 g silica gel; sample was loaded with CH₂Cl₂; elutedwith 60-100% EtOAc/hexanes) to afford (S)-1-tert-butyl 5-methyl1H-pyrazole-1,5(4H,5H)-dicarboxylate as a colorless oil (861 mg). ¹H NMR(CDCl₃, δ=7.24 ppm, 400 MHz): 4.39 (app br t, J=7.7, 1H), 3.74 (s, 3H),3.15-3.02 (m, 2H), 2.64 (s, 3H), 2.48-2.40 (m, 1H), 2.30-2.21 (m, 1H),1.45 (s, 9H). LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₁H₂₀N₂NaO₄: 267.13.found 267.28.

Lithium (S)-2-(tert-butoxycarbonyl)pyrazolidine-3-carboxylate

A water (5 mL) solution of LiOH (0.146 g, 6.09 mmol) was added to amethanol (5 mL) solution of (S)-1-tert-butyl 5-methyl1H-pyrazole-1,5(4H,5H)-dicarboxylate (0.76 g, 3.11 mmol), and stirred atambient conditions for ˜7 h. The reaction mixture was cooled with anice-water bath, and HCl/H₂O (3 mL of 1.00 N; 3.0 mmol) was addeddropwise and stirred for a few minutes. Then, the volatile component wasremoved in vacuo and the resultant viscous oil was exposed to highvacuum to afford lithium(S)-2-(tert-butoxycarbonyl)pyrazolidine-3-carboxylate as a white foam,which was used without further purification. ¹H NMR (DMSO-d₆, δ=2.50ppm, 400 MHz) for crude sample: 3.98 (dd, J=8.5, 6.3, 1H), 2.86-2.74 (m,2H), 2.45 (s, 3H), 2.25-2.17 (m, 1H), 2.10-2.02 (m, 1H), 1.35 (s, 9H).LC-MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₉N₂O₄: 231.13. found 231.21.

2-Amino-1-(4-(6-(2-aminoacetyl)naphthalen-2-yl)phenyl)ethanone

A slurry of2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (1.0 g,2.2 mmol) and hexamethylenetetramine (0.660 g, 4.71 mmol) were slurriedinto chloroform (30 mL) and heated at 50° C. for 2 h. The reaction wascooled to rt and the solids were collected by filtration (rinsed withchloroform, 3×25 mL). The resulting bright yellow solid was slurriedinto MeOH (15.0 mL) and then conc HCl (3.0 mL, 99 mmol) was addeddropwise and the reaction was stirred in the dark for 2 d. The reactionwas concentrated to a solid which was slurried into water and stirredfor 1 h. The solids were collected by filtration and the cake was driedin a vacuum oven to yield an HCl salt of2-amino-1-(4-(6-(2-aminoacetyl)naphthalen-2-yl)phenyl)ethanone (787 mg).LC-MS retention time 2.342 min; m/z 319.09 (MH+). LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX®Luna 3 u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1min, and an analysis time of 5 min where Solvent A was 5% MeOH/95%H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mMammonium acetate. MS data was determined using a MICROMASS® Platform forLC in electrospray mode.

(S)-tert-Butyl5-(2-(4-(6-(2-((S)-2-(tert-butoxycarbonyl)-1-methylpyrazolidine-3-carboxamido)acetyl)naphthalen-2-yl)phenyl)-2-oxoethylcarbamoyl)-2-methylpyrazolidine-1-carboxylate

HATU (1577 mg, 4.15 mmol) was added to a stirred solution of a n HClsalt of 2-amino-1-(4-(6-(2-aminoacetyl)naphthalen-2-yl)phenyl)ethanone(773 mg, 1.98 mmol) and lithium(S)-2-(tert-butoxycarbonyl)-1-methylpyrazolidine-3-carboxylate (980 mg,4.15 mmol) in DMF (15 mL) and Hunig's Base (2.070 mL, 11.85 mmol) andthe reaction mixture was stirred for 2 h. The reaction was concentratedto ˜20% volume, diluted with MeOH, filtered and purified by HPLC(MeOH/water with an ammonium acetate buffer) to yield (S)-tert-butyl5-(2-(4-(6-(2-((S)-2-(tert-butoxycarbonyl)-1-methylpyrazolidine-3-carboxamido)acetyl)naphthalen-2-yl)phenyl)-2-oxoethylcarbamoyl)-2-methylpyrazolidine-1-carboxylate(537 mg) as a bright yellow solid. LC-MS retention time 3.758 min; m/z741.55 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

(S)-tert-Butyl5-(5-(4-(6-(2-((S)-2-(tert-butoxycarbonyl)-1-methylpyrazolidin-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-methylpyrazolidine-1-carboxylate

In a 25 mL pressure tube, (S)-tert-butyl5-(2-(4-(6-(2-((S)-2-(tert-butoxycarbonyl)-1-methylpyrazolidine-3-carboxamido)acetyl)naphthalen-2-yl)phenyl)-2-oxoethylcarbamoyl)-2-methylpyrazolidine-1-carboxylate(420 mg, 0.565 mmol) and ammonium acetate (872 mg, 11.3 mmol) wereslurried into xylenes (7 mL). The reaction vessel was sealed and heatedat 135° C. for 5 h then at rt ON. The crude reaction was diluted with ½sat aq. NaHCO₃ (40 mL) and extracted with DCM (3×30 mL). The combineorganics were dried (MgSO₄), filtered and concentrated to yield(S)-tert-butyl5-(5-(4-(6-(2-((S)-2-(tert-butoxycarbonyl)-1-methylpyrazolidin-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-methylpyrazolidine-1-carboxylate(95 mg, ˜80% purity) as a dark yellow glass. LC-MS retention time 4.026min; m/z 703.63 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.32 (s, 1H), 8.28 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.10 (d, J=8.8Hz, 1H), 7.86-8.03 (m, 8H), 5.31-5.39 (m, 2H), 3.22-3.35 (m, 4H),2.82-2.93 (m, 2H), 2.77 (s, 3H), 2.76 (s, 3H), 2.53-2.65 (m, 2H), 1.43(s, 18H).

Condition 1 Column=PHENOMENEX®, 2.0×50 mm, 3 μm Start % B=0 Final %B=100

Gradient time=4 minStop time=5 minFlow Rate=0.8 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% waterSolvent B=0.1% TFA in 90% methanol/10% waterOven temp.=40° C.

Condition 2 Column=Sunfire, C18, 3.0×150 mm, 3.5 μm Start % B=0 Final %B=100

Gradient time=15 minStop time=18 minFlow Rate=1 mL/min

Wavelength 1=220 nm Wavelength 2=254 nm

Solvent A=0.1% TFA in 5% MeCN/95% waterSolvent B=0.1% TFA in 95% MeCN/5% water

(S)-2-(4-(6-(2-((S)-2-(tert-Butoxycarbonylamino)-3,3-dimethylbutanoyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate

To a solution of2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone (0.2 g,0.448 mmol) and (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoicacid (0.207 g, 0.897 mmol) in DCM was added DIPEA (0.172 mL, 0.986mmol). The reaction mixture was stirred at rt for 16 h and then dilutedwith EtOAc, washed with sat. NaHCO₃, water, sat. NaCl and dried overanhydrous Na₂SO₄. Then it was filtered and concentrated to yield(S)-2-(4-(6-(2-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate as a pale yellowsolid. LC-MS (Cond. 1): [M+H]⁺ 747.50, R_(t)=4.67 min.

tert-Butyl(S)-1-(5-(4-(6-(2-((S)-2,2-dimethyl-1-(tert-butoxycarbonylamino)propyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropylcarbamate

In a sealed tube, a reaction mixture of(S)-2-(4-(6-(2-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyloxy)acetyl)naphthalen-2-yl)phenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate (0.35 g, 0.469 mmol)in xylenes (5 mL) and ammonium acetate (0.361 g, 4.69 mmol) was heatedat 130° C. for 3 h. The reaction mixture was diluted with EtOAc andwater. The organic layer was washed with sat. NaHCO₃ and sat. NaCl,dried over anhydrous Na₂SO₄, filtered and concentrated. The residue wascharged into a 40 g silica gel cartridge which was eluted with a 15 mingradient of 0-100% EtOAc/Hex to yield tert-butyl(S)-1-(5-(4-(6-(2-((S)-2,2-dimethyl-1-(tert-butoxycarbonylamino)propyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropylcarbamate(0.2 g) as a yellow solid. LC-MS (Cond. 1): [M+H]⁺ 707.6, R_(t)=3.44min.

(S)-1-(5-(4-(6-(2-((S)-1-Amino-2,2-dimethylpropyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine

To a reaction mixture of tert-butyl(S)-1-(5-(4-(6-(2-((S)-2,2-dimethyl-1-(tert-butoxycarbonylamino)propyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropylcarbamate(0.2 g, 0.283 mmol) in DCM was added 4M hydrogen chloride in dioxane (2mL, 8 mmol). The reaction mixture was stirred at rt for 4 h and thenconcentrated to dryness to yield an HCl salt of(S)-1-(5-(4-(6-(2-((S)-1-amino-2,2-dimethylpropyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amineas a yellow solid. LC-MS (Cond. 1): [M+H]⁺ 507.43, R_(t)=3.241 min.

EXAMPLES

Methyl((1S)-1-(((2S)-2-(5-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (59 mg, 0.15 mmol) was added to a mixture of a TFA salt of2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (37mg), diisopropylethylamine (68 μL, 0.40 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (27 mg, 0.15 mmol) inDMF (2 mL) and the resulting mixture was stirred at ambient conditionsfor 2.5 hours. The reaction mixture was diluted with methanol (2 mL) andwater (2 mL) and stirred for 15 min. The volatile component was removedin vacuo and the residue was purified twice by a reverse phase HPLC(water/acetonitrile/TFA) and reverse phase HPLC(water/acetonitrile/NH₄OAc) to provide the desired product which wassuspended in methanol and TFA. The volatiles were removed in vacuo toafford a TFA salt of methyl((1S)-1-(((2S)-2-(5-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(11.3 mg) as tan solid. LC-MS retention time 1.34 min; calcd. forC₄₆H₅₂N₈O₆ 812.4. found m/z 813.42 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.31 (s, 2H), 8.03-8.10 (m, 4H),7.96-8.02 (m, Hz, 2H), 7.89 (dd, J=8.6, 1.5 Hz, 2H), 7.85 (m, 2H), 5.36(t, J=7.0 Hz, 2H), 4.22-4.32 (m, 2H), 4.09-4.19 (m, 2H), 3.89-4.00 (m,2H), 3.63-3.74 (m, 6H), 2.56-2.70 (m, 2H), 2.31-2.40 (m, 2H), 2.19-2.31(m, 4H), 2.08 (dd, J=13.6, 6.9 Hz, 2H), 0.95 (d, J=7.0 Hz, 6H), 0.89 (d,J=6.7 Hz, 6H).

Methyl((1S)-1-(((2S)-2-(5-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (82 mg, 0.217 mmol) was added to a TFA salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (69mg), diisopropylethylamine (126 μL, 0.723 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (51 mg, 0.29 mmol) inDMF (2 mL) and the resulting mixture was stirred at ambient conditionsfor 2.5 hours. The reaction mixture was diluted with methanol (2 mL) andwater (2 mL). Then the volatile component was removed in vacuo and theresidue was purified by a reverse phase HPLC (water/acetonitrile/TFA) toprovide a TFA salt of methyl((1S)-1-(((2S)-2-(5-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(47 mg) as tan solid. LC-MS retention time 1.30 min; calcd. forC₄₆H₅₂N₈O₆: 812.40. found m/z 813.42 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.25 (s, 2H), 8.07-8.16 (m, 4H), 8.02 (m,J=8.6 Hz, 2H), 7.91 (m, J=8.6 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H), 5.37 (t,J=7.2 Hz, 2H), 4.28 (d, J=7.0 Hz, 2H), 4.09-4.18 (m, 2H), 3.90-4.01 (m,2H), 3.63-3.73 (m, 6H), 2.57-2.70 (m, 2H), 2.32-2.45 (m, 2H), 2.19-2.32(m, 4H), 2.09 (dq, J=13.6, 6.9 Hz, 2H), 0.95 (d, J=6.7 Hz, 6H), 0.89 (d,J=6.7 Hz, 6H).

Methyl((1S)-1-(((2S)-2-(4-(4-(6-(2-(1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (39 mg, 0.10 mmol) was added to a mixture of a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-benzo[d]imidazole(50 mg), diisopropylethylamine (89 μL, 0.51 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (27 mg, 0.15 mmol) inDMF (2 mL) and the resulting mixture was stirred at ambient conditionsfor 2.5 hours. The reaction mixture was diluted with methanol (2 mL) andwater (2 mL). The volatile component was removed in vacuo and theresidue was purified by a reverse phase HPLC (water/acetonitrile/TFA) toprovide a TFA salt of methyl((1S)-1-(((2S)-2-(4-(4-(6-(2-(1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(31.4 mg) as tan solid. LC-MS retention time 1.37 min; calcd. forC₄₈H₅₄N₈O₆ 838.42. found m/z 839.36 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.23-8.28 (m, 2H), 8.08-8.15 (m, 3H), 8.02 (d,J=8.6 Hz, 1H), 7.95-8.00 (m, 2H), 7.85-7.95 (m, 6H), 5.40 (t, J=7.2 Hz,1H), 5.29 (t, J=7.5 Hz, 1H), 4.29 (dd, J=19.4, 7.2 Hz, 2H), 4.10-4.19(m, 2H), 3.96-4.03 (m, 1H), 3.87-3.96 (m, 1H), 3.69 (m, 6H), 2.55-2.73(m, 2H), 2.04-2.42 (m, 8H), 0.89-1.05 (m, 12H).

Methyl((1S)-1-(((2S)-2-(4-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (29 mg, 0.076 mmol) was added to a mixture of a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(7-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-benzo[d]imidazole(25 mg), diisopropylethylamine (45 μL, 0.26 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (13 mg, 0.76 mmol) inDMF (2 mL) and the resulting mixture was stirred at ambient conditionsfor 2.5 hours. The reaction mixture was diluted with methanol (2 mL) andwater (2 mL). The volatile component was removed in vacuo and theresidue was purified by a reverse phase HPLC (water/acetonitrile/TFA) toprovide a TFA salt of methyl((1S)-1-(((2S)-2-(4-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(14.2 mg) as yellow solid. LC-MS retention time 1.40 min; calcd. forC₄₈H₅₄N₈O₆ 838.42. found m/z 839.36 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.33 (br s, 2H), 8.13 (s, 1H),8.03-8.10 (m, 3H), 8.00 (d, J=8.2 Hz, 2H), 7.86-7.94 (m, 6H), 5.40 (t,J=7.2 Hz, 1H), 5.29 (t, J=7.6 Hz, 1H), 4.31 (d, J=7.3 Hz, 1H), 4.27 (d,J=7.3 Hz, 1H), 4.10-4.20 (m, 2H), 3.85-4.10 (m, 2H), 3.69 (s, 6H),2.55-2.74 (m, 2H), 2.03-2.37 (m, 8H), 0.85-1.05 (m, 12H).

Methyl((1S)-2-((2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

HATU (74.5 mg, 0.196 mmol) was added to a stirring solution of a TFAsalt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (40mg), (S)-2-(methoxycarbonylamino)propanoic acid (28.8 mg, 0.196 mmol)and DIEA (0.114 mL, 0.653 mmol) in DMF (2 mL). The reaction was stirred9 h at room temperature, diluted with MeOH (2 mL) and water (2 mL),concentrated to remove the volatiles and purified by preparative HPLC(acetonitrile/water with 0.1% TFA) to afford a TFA salt of methyl((1S)-2-((2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate(35.9 mg) as white solid. LC-MS retention time 1.12 min; calcd. forC₄₂H₄₄N₈O₆ 756.34. found m/z 757.20 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.22-8.30 (m, 2H), 8.08-8.18 (m,4H), 7.99-8.07 (m, 2H), 7.83-7.96 (m, 4H), 5.44 (dd, J=8.6, 5.2 Hz, 2H),4.56 (q, J=6.9 Hz, 2H), 4.0-4.09 (m, 2H), 3.94-4.02 (m, 2H), 3.61-3.75(m, 6H), 2.58-2.72 (m, 2H), 2.21-2.38 (m, 6H), 1.32-1.45 (m, 6H).

Dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

HATU (74.5 mg, 0.196 mmol) was added to a stirring solution of a TFAsalt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (40mg), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (41.0 mg, 0.196mmol) and DIEA (0.114 mL, 0.653 mmol) in DMF (2 mL). The reaction wasstirred 9 h at room temperature, diluted with MeOH (2 mL) and water (2mL), concentrated to remove the volatiles and purified by preparativeHPLC (acetonitrile/water with 0.1% TFA) and then by preparative HPLC(acetonitrile/water with 10 mM ammonium acetate) to afford dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate(32.3 mg) as white solid. LC-MS retention time 1.43 min; calcd. forC₅₂H₄₈N₈O₆ 880.37. found m/z 881.23 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.25-8.35 (m, 2H), 8.12-8.21 (m,4H), 8.05-8.12 (m, 2H), 7.90-8.00 (m, 4H), 7.38-7.54 (m, 10H), 5.62 (s,2H), 5.38-5.53 (m, 2H), 4.04-4.18 (m, 2H), 3.67 (s, 6H), 2.34-2.41 (m,2H), 2.46-2.58 (m, 2H), 2.15-2.35 (m, 4H), 2.02-2.13 (m, 2H).

5,5′-(2,6-Naphthalenediyl)bis(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-benzimidazole)

HATU (74.5 mg, 0.196 mmol) was added to a stirring solution of a TFAsalt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (40mg), (R)-2-phenyl-2-(piperidin-1-yl)acetic acid (43.0 mg, 0.196 mmol)and DIEA (0.114 mL, 0.653 mmol) in DMF (2 mL). The reaction was stirred9 h at room temperature, diluted with MeOH (2 mL) and water (2 mL),concentrated to remove the volatiles and purified by preparative HPLC(acetonitrile/water with 0.1% TFA) and then by preparative HPLC(acetonitrile/water with 10 mM ammonium acetate) to afford5,5′-(2,6-naphthalenediyl)bis(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-benzimidazole)(44.3 mg) as white solid. LC-MS retention time 1.18 min; calcd. for[M+H]⁺ C₅₈H₅₀N₈O₂ 900.48. found m/z 451.33 [½ M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA.

(1R)-2-((2S)-2-(5-(6-(2-((2S)-1-((2R)-2-(Dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

HATU (74.5 mg, 0.196 mmol) was added to a stirring solution of a TFAsalt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (40mg, 0.065 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid (35.1 mg) andDIEA (0.114 mL, 0.653 mmol) in DMF (2 mL). The reaction was stirred 9 hat room temperature, diluted with MeOH (2 mL) and water (2 mL),concentrated to remove the volatiles and purified by preparative HPLC(acetonitrile/water with 0.1% TFA) and then by preparative HPLC(acetonitrile/water with 10 mM ammonium acetate) to afford(1R)-2-((2S)-2-(5-(6-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine(44.3 mg) as off-white solid. LC-MS retention time 1.07 min; calcd. forC₅₂H₅₂N₈O₂ 820.42. found m/z 821.29 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.31 (s, 2H), 8.20-8.24 (m, 2H),8.13-8.20 (m, 2H), 8.07-8.13 (m, 2H), 7.89-8.05 (m, 4H), 7.60-7.70 (m,10H), 5.55-5.59 (m, 2H), 5.52 (dd, J=8.7, 3.8 Hz, 2H), 4.11-4.19 (m,2H), 2.42-3.18 (m, 13H), 2.17-2.36 (m, 5H), 1.98-2.08 (m, 4H).

Methyl((1S,2R)-2-methoxy-1-(((2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

HATU (74.5 mg, 0.196 mmol) was added to a stirring solution of a TFAsalt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (40mg), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (37.4 mg,0.196 mmol) and DIEA (0.114 mL, 0.653 mmol) in DMF (2 mL). The reactionwas stirred 9 h at room temperature, diluted with MeOH (2 mL) and water(2 mL), concentrated to remove the volatiles and purified by preparativeHPLC (acetonitrile/water with 0.1% TFA) and then by preparative HPLC(acetonitrile/water with 10 mM ammonium acetate) to afford methyl((1S,2R)-2-methoxy-1-(((2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate(9.3 mg) as white solid. LC-MS retention time 1.22 min; calcd. for[M+H]⁺ C₄₆H₅₂N₈O₈ 844.39. found m/z 845.25 [M+H]⁺. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a WatersSunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.10-8.21 (m, 2H), 7.99-8.08 (m, 2H),7.83-7.96 (m, 4H), 7.58-7.77 (m, 4H), 5.70-5.75 (m, 0.4H), 5.35 (dd,J=7.9, 4.9 Hz, 1.6H), 4.58-4.61 (m, 0.2H), 4.51 (d, J=4.9 Hz, 1.5H),4.37-4.43 (m, 0.3H), 3.89-4.08 (m, 3H), 3.61-3.78 (m, 7H), 3.38-3.45 (m,2H), 3.23-3.31 (m, 5H), 1.93-2.57 (m, 9H), 1.10-1.28 (m, 6H).

Methyl((1S)-3-methoxy-1-(((2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

HATU (74.5 mg, 0.196 mmol) was added to a stirring solution of a TFAsalt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (40mg), (S)-4-methoxy-2-(methoxycarbonylamino)butanoic acid (37.4 mg, 0.196mmol) and DIEA (0.114 mL, 0.653 mmol) in DMF (2 mL). The reaction wasstirred 9 h at room temperature, diluted with MeOH (2 mL) and water (2mL), concentrated to remove the volatiles and purified by preparativeHPLC (acetonitrile/water with 0.1% TFA) to afford a TFA salt of methyl((1S)-3-methoxy-1-(((2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate(28.6 mg) as yellow solid. LC-MS retention time 1.18 min; calcd. for[M+H]⁺ C₄₆H₅₂N₈O₈ 844.39. found m/z 845.22 [M+H]⁺. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a WatersSunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.23-8.30 (m, 2H), 8.09-8.18 (m,4H), 8.00-8.09 (m, 2H), 7.84-7.97 (m, 4H), 5.84-5.90 (m, 0.2H), 5.44(dd, J=8.2, 4.9 Hz, 1.8H), 4.65 (dd, J=9.2, 4.0 Hz, 1.8H), 4.38-4.45 (m,0.2H), 3.91-4.11 (m, 4H), 3.66-3.78 (m, 6H), 3.39-3.55 (m, 4H),3.27-3.38 (m, 7H), 2.59-2.75 (m, 2H), 2.25-2.40 (m, 5H), 2.16 (dddd,J=14.3, 7.0, 6.8, 4.3 Hz, 2H), 1.74-1.93 (m, 2H).

Dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1S)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate

HATU (74.5 mg, 0.196 mmol) was added to a stirring solution of a TFAsalt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (40mg, 0.065 mmol), (S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid(33.9 mg, 0.196 mmol) and DIEA (0.114 mL, 0.653 mmol) in DMF (2 mL). Thereaction was stirred 9 h at room temperature, diluted with MeOH (2 mL)and water (2 mL), concentrated to remove the volatiles and purified bypreparative HPLC (acetonitrile/water with 0.1% TFA) to afford a TFA saltof dimethyl(1S,1′S)-2,2′-((2S,2′S)-2,2′-(5,5′-(naphthalene-2,6-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(1-cyclopropyl-2-oxoethane-2,1-diyl)dicarbamate (34.9 mg, 0.038 mmol, 58% yield) as whitesolid. LC-MS retention time 1.23 min; calcd. for C₄₆H₄₈N₈O₆ 808.37.found m/z 809.22 [M+H]⁺. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Sunfire 5 u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, agradient time of 3 min, a hold time of 1 min and an analysis time of 4min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and SolventB was 90% acetonitrile/10% water/0.1% TFA. ¹H NMR (TFA salt, 500 MHz,MeOD) δ ppm 8.20-8.29 (m, 2H), 8.07-8.16 (m, 4H), 7.98-8.07 (m, 2H),7.84-7.95 (m, 4H), 5.37-5.48 (m, 2H), 4.03-4.13 (m, 2H), 3.87-4.03 (m,4H), 3.64-3.74 (m, 6H), 2.65-2.74 (m, 2H), 2.20-2.40 (m, 6H), 1.09-1.22(m, 2H), 0.47-0.67 (m, 6H), 0.30-0.46 (m, 2H).

Dimethyl(2,7-naphthalenediylbis(1H-benzimidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

HATU (56.2 mg, 0.148 mmol) was added to a stirred solution of a TFA saltof2-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(47 mg), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (30.9 mg,0.148 mmol) and DIEA (0.086 mL, 0.49 mmol) in DMF (2 mL). The reactionwas stirred 4 h at room temperature, diluted with MeOH (2 mL) and water(2 mL) concentrated to remove the volatiles and purified by preparativeHPLC (acetonitrile/water with 0.1% TFA) to afford a TFA salt of dimethyl(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(naphthalene-2,7-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate(38 mg) as light yellow solid. LC-MS retention time 1.45 min; calcd. forC₅₂H₄₈N₈O₆ 880.37. found m/z 881.26 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.31-8.39 (m, 2H), 8.03-8.17 (m, 6H),7.84-8.00 (m, 4H), 7.33-7.53 (m, 10H), 5.55-5.63 (m, 2H), 5.40-5.54 (m,2H), 4.01-4.17 (m, 2H), 3.67 (s, 6H), 3.27-4.41 (m, 2H), 2.44-2.75 (m,2H), 2.01-2.33 (m, 6H).

Methyl((1S)-2-((2S)-2-(5-(7-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

HATU (56.2 mg, 0.148 mmol) was added to a stirred solution of a TFA saltof2-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(47 mg), (S)-2-(methoxycarbonylamino)propanoic acid (21.7 mg, 0.148mmol) and DIEA (0.086 mL, 0.49 mmol) in DMF (2 mL). The reaction wasstirred 5 h at room temperature, diluted with MeOH (2 mL) and water (2mL) concentrated to remove the volatiles and purified by preparativeHPLC (acetonitrile/water with 0.1% TFA) and then by preparative HPLC(acetonitrile/water with 10 mM ammonium acetate) to afford methyl((1S)-2-((2S)-2-(5-(7-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate(20.9 mg) as white solid. LC-MS retention time 1.16 min; calcd. forC₄₂H₄₄N₈O₆ 756.34. found m/z 757.27 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.16-8.24 (m, 2H), 7.87-8.02 (m, 4H),7.80-7.87 (m, 2H), 7.60-7.75 (m, 4H), 5.42-5.46 (m, 0.3H), 5.34 (dd,J=7.9, 4.0 Hz, 1.7H), 4.55 (q, J=7.0 Hz, 1.7H), 4.31-4.37 (m, 0.3H),3.80-3.98 (m, 4H), 3.67 (s, 5H), 3.47 (s, 1H), 2.39-2.55 (m, 2H),2.04-2.36 (m, 4H), 1.92-2.01 (m, 2H), 1.31-1.42 (m, 6H).

Methyl((1R)-1-(((2S)-2-(5-(7-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (56.2 mg, 0.148 mmol) was added to a stirred solution of a TFA saltof2-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(47 mg), (R)-2-(methoxycarbonylamino)-3-methylbutanoic acid (25.9 mg,0.148 mmol) and DIEA (0.086 mL, 0.49 mmol) in DMF (2 mL). The reactionwas stirred 5 h at room temperature, diluted with MeOH (2 mL) and water(2 mL) concentrated to remove the volatiles and purified by preparativeHPLC (acetonitrile/water with 0.1% TFA) and then by preparative HPLC(acetonitrile/water with 10 mM ammonium acetate) to afford a TFA salt ofmethyl((1R)-1-(((2S)-2-(5-(7-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(25 mg) as beige solid. LC-MS retention time 1.36 min; calcd. forC₄₆H₅₂N₈O₆ 812.40. found m/z 813.36 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.33 (s, 2H), 8.07-8.13 (m, 4H),8.05 (dd, J=8.5, 1.2 Hz, 2H), 7.84-7.96 (m, 4H), 5.49 (dd, J=8.6, 3.7Hz, 2H), 4.36 (d, J=7.3 Hz, 2H), 4.15-4.23 (m, 2H), 3.83-3.97 (m, 2H),3.72 (s, 6H), 2.58-2.71 (m, 2H), 2.21-2.38 (m, 6H), 2.05-2.18 (m, 2H),1.07 (d, J=6.7 Hz, 6H), 1.04 (d, J=6.7 Hz, 6H).

5,5′-(2,7-Naphthalenediyl)bis(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-benzimidazole)

HATU (56.2 mg, 0.148 mmol) was added to a stirred solution of a TFA saltof2-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(47 mg), (R)-2-phenyl-2-(piperidin-1-yl)acetic acid (32.4 mg, 0.148mmol) and DIEA (0.086 mL, 0.49 mmol) in DMF (2 mL). The reaction wasstirred 5 h at room temperature, diluted with MeOH (2 mL) and water (2mL) concentrated to remove the volatiles and purified by preparativeHPLC (acetonitrile/water with 0.1% TFA) and then by preparative HPLC(acetonitrile/water with 10 mM ammonium acetate) to afford5,5′-(2,7-naphthalenediyl)bis(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-benzimidazole)(16.4 mg) as white solid. LC-MS retention time 1.21 min; calcd. for[M+H]⁺ C₅₈H₆₀N₈O₆ 900.48. found m/z 451.43 ½[M+H]⁺. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a WatersSunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (400 MHz, MeOD) δ ppm 8.18-8.28 (m, 2H), 7.96-8.05 (m, 2.2H), 7.92(d, J=1.0 Hz, 1.5H), 7.80-7.90 (m, 2.2H), 7.65-7.76 (m, 3.8H), 7.55-7.64(m, 3.2H), 7.46-7.55 (m, 4.5H), 6.85-6.97 (m, 1.6H), 6.76-6.83 (m, 1H),5.65-5.70 (m, 0.5H), 5.28 (dd, J=7.5, 3.3 Hz, 1.5H), 4.48 (br s, 0.5H),4.02-4.12 (m, 1.5H), 3.90-3.98 (m, 0.5H), 3.74-3.84 (m, 0.5H), 3.25-3.40(m, 3H), 2.51-2.93 (m, 8H), 1.89-2.33 (m, 8H), 1.62-1.75 (m, 8H),1.47-1.59 (m 4H).

Methyl((1S)-1-(((2S)-2-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (40 mg, 0.11 mmol) was added to a mixture of a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazole(32 mg), diisopropylethylamine (62 μL, 0.35 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19 mg, 0.106 mmol)in DMF (2 mL) and the resulting mixture was stirred at ambientconditions for 9 hours. The reaction mixture was diluted with methanol(2 mL) and water (2 mL). The volatile component was removed in vacuo andthe residue was purified by reverse phase HPLC (once withwater/acetonitrile 10 mM ammonium acetate and twice withwater/acetonitrile 0.1% TFA) to provide a TFA salt of methyl((1S)-1-(((2S)-2-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(21 mg) as white solid. LC-MS retention time 1.17 min; calcd. forC₄₂H₅₀N₈O₆ 762.39. found m/z 763.34 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.30 (s, 1H), 8.27 (s, 1H), 8.15 (d, J=8.9 Hz,1H), 8.10 (d, J=8.9 Hz, 1H), 8.07 (s, 1H), 7.94-8.01 (m, 3H), 7.82-7.89(m, 2H), 5.38 (t, J=7.2 Hz, 1H), 5.31 (t, J=7.6 Hz, 1H), 4.28 (dd,J=14.5, 7.2 Hz, 2H), 4.15 (br s, 2H), 3.86-4.01 (m, 2H), 3.69 (s, 6H),2.55-2.69 (m, 2H), 2.19-2.39 (m, 6H), 2.04-2.15 (m, 2H), 0.86-1.05 (m,12H).

Methyl((1S)-1-(((2S)-2-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (20 mg, 0.053 mmol) was added to a mixture of a TFA salt of2-((S)-pyrrolidin-2-yl)-6-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-1H-benzo[d]imidazole(16 mg), diisopropylethylamine (31 μL, 0.18 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (9.3 mg, 0.053 mmol)in DMF (2 mL) and the resulting mixture was stirred at ambient for 9hours. The reaction mixture was diluted with methanol (2 mL) and water(2 mL). The volatile component was removed in vacuo and the residue waspurified by a reverse phase HPLC (water/acetonitrile 0.1% TFA) toprovide a TFA salt of methyl((1S)-1-(((2S)-2-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(7.9 mg) as white solid. LC-MS retention time 1.20 min; calcd. forC₄₂H₅₀N₈O₆ 762.39. found m/z 763.35 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. ¹HNMR (500 MHz, MeOD) δ ppm 8.35 (s, 1H), 8.25 (s, 1H), 8.09 (dd, J=8.4,3.2 Hz, 2H), 8.04 (s, 1H), 7.89-8.00 (m, 3H), 7.77-7.87 (m, 2H), 5.37(t, J=7.0 Hz, 1H), 5.30 (t, J=7.3 Hz, 1H), 4.28 (dd, J=15.4, 7.2 Hz,2H), 4.08-4.20 (m, 2H), 3.86-4.01 (m, 2H), 3.69 (s, 6H), 2.56-2.68 (m,3H), 2.39-2.02 (m, 7H), 0.87-1.04 (m, 12H).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (218 mg, 0.574 mmol) was added to a mixture of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(100 mg), diisopropylethylamine (334 μL, 1.91 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (101 mg, 0.574 mmol)in DMF (2 mL) and the resulting mixture was stirred at ambient for 4hours. The reaction mixture was diluted with methanol (2 mL) and water(2 mL). Then, the volatile component was removed in vacuo and theresidue was purified by a reverse phase HPLC (water/acetonitrile 0.1%TFA) to provide a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(85 mg) as yellow solid. LC-MS retention time 1.33 min; calcd. forC₄₈H₅₂N₈O₆: 836.4. found m/z 837.32 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5 uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min and ananalysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (500 MHz, MeOD) δ ppm 8.22 (s, 2H), 8.05-8.13 (m, 4H),7.96-8.02 (m, 2H), 7.82-7.92 (m, 4H), 5.22-5.32 (m, 2H), 4.59 (d, J=6.4Hz, 2H), 3.86 (t, J=6.0 Hz, 2H), 3.60-3.75 (m, 6H), 2.66-2.79 (m, 2H),2.54 (m, 2H), 2.16-2.26 (m, 2H), 2.02-2.16 (m, 2H), 1.10-1.16 (m, 2H),0.98-1.05 (m, 6H), 0.94-0.97 (m, 2H), 0.91 (d, J=6.7 Hz, 6H).

(1R)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2R)-2-(Diethylamino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-N,N-diethyl-2-oxo-1-phenylethanamine

HATU (109 mg, 0.287 mmol) was added to a mixture of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(50 mg), diisopropylethylamine (0.167 mL, 0.957 mmol) and(R)-2-(diethylamino)-2-phenylacetic acid, HCl (70.0 mg, 0.287 mmol) inDMF (2 mL) and the resulting mixture was stirred at ambient for 5 hours.The reaction mixture was diluted with methanol (2 mL) and water (2 mL).Then, the volatile component was removed in vacuo and the residue waspurified by a reverse phase HPLC (water/acetonitrile 0.1% TFA) then byreverse phase HPLC (water/acetonitrile 10 mM ammonium acetate) andfinally by reverse phase HPLC (water/acetonitrile 0.1% TFA) to provide aTFA salt of(1R)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-42R)-2-(diethylamino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-N,N-diethyl-2-oxo-1-phenylethanamine(25.2 mg) as white powder. LC-MS retention time 1.15 min; calcd. for[M+H]⁺ C₅₈H₆₀N₈O₂: 900.48. found m/z 451.46 [½ M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.27 (s, 2H), 8.08-8.17 (m,4H), 7.96 (td, J=8.7, 1.5 Hz, 4H), 7.87 (d, J=8.6 Hz, 2H), 7.68-7.72 (m,4H), 7.57-7.68 (m, 6H), 5.79 (s, 2H), 5.23 (dd, J=9.0, 6.3 Hz, 2H),3.95-4.05 (m, 2H), 3.25-3.48 (m, 4H), 3.06 (br s, 4H), 2.43-2.61 (m,4H), 2.01-2.11 (m, 2H), 1.31 (t, J=6.9 Hz, 12H), 0.62 (ddd, J=8.7, 6.0,5.8 Hz, 2H), −0.21 (td, J=5.7, 2.4 Hz, 2H).

Example 20 Methyl((1R)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamateand Example 21 Dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

HATU (109 mg, 0.287 mmol) was added to a mixture of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(50 mg), diisopropylethylamine (0.167 mL, 0.957 mmol) and(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (60.0 mg, 0.287 mmol)in DMF (2 mL) and the resulting mixture was stirred at ambient for 5hours. The reaction mixture was diluted with methanol (2 mL) and water(2 mL). Then, the volatile component was removed in vacuo and theresidue was purified by a reverse phase HPLC (water/acetonitrile 0.1%TFA) then by reverse phase HPLC (water/acetonitrile 10 mM ammoniumacetate) and finally by reverse phase HPLC (water/acetonitrile 0.1% TFA)to provide a TFA salt of methyl((1R)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate(6.9 mg) as white solid and a TFA salt of dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate(12.5 mg) as white solid.

Analytical data for Example 20: LC-MS retention time 1.46 min; calcd.for C₅₄H₄₈N₈O₆: 904.37. found m/z 453.35 [½ M+H]⁺. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a WatersSunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.28 (d, J=4.6 Hz, 2H),8.15 (d, J=8.6 Hz, 2H), 8.12 (s, 1H), 8.07 (s, 1H), 8.03 (t, J=8.9 Hz,2H), 7.92-7.98 (m, 2H), 7.90 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H),7.48-7.54 (m, 2H), 7.37-7.48 (m, 8H), 5.85 (s, 1H), 5.78 (s, 1H), 5.39(dd, J=9.0, 6.3 Hz, 1H), 5.29 (dd, J=9.2, 5.8 Hz, 1H), 3.91-3.97 (m,1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.52-3.61 (m, 1H), 2.73 (dd, J=13.7,9.2 Hz, 1H), 2.46-2.65 (m, 3H), 2.06-2.14 (m, 1H), 1.98-2.06 (m, 1H),1.23-1.30 (m, 1H), 1.10 (br s, 1H), 0.66-0.72 (m, 1H), 0.01-0.10 (m,1H).

Analytical data for Example 21: LC-MS retention time 1.48 min; calcd.for [M+H]⁺ C₅₄H₄₈N₈O₆: 904.37. found m/z 453.35 [½ M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 minand an analysis time of 4 min where Solvent A was 10% acetonitrile/90%water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.29 (s, 2H), 8.16 (d,J=8.6 Hz, 2H), 8.11 (s, 2H), 8.01-8.06 (m, 2H), 7.95 (d, J=8.6 Hz, 2H),7.90 (m, J=8.6 Hz, 2H), 7.48-7.55 (m, 4H), 7.36-7.48 (m, 6H), 5.85 (s,2H), 5.29 (dd, J=9.2, 5.8 Hz, 2H), 3.92-3.97 (m, 2H), 3.66 (s, 6H),2.55-2.66 (m, 2H), 2.51 (ddd, J=13.3, 6.6, 6.4 Hz, 2H), 1.97-2.07 (m,2H), 0.63-0.74 (m, 2H), −0.02-0.10 (m, 2H).

Example 22 Methyl((1S)-1-(((2S)-2-(6-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyridin-6-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyridin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamateand Example 23 Methyl((1S)-1-(((2R)-2-(6-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyridin-6-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyridin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (63.5 mg, 0.167 mmol) was added to a stirred slurry of ahydrochloride salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-3H-imidazo[4,5-b]pyridin-6-yl)naphthalene(45 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (29.3 mg,0.167 mmol) in DMF (1 mL) and DIPEA (0.122 mL, 0.696 mmol). The reactionmixture was stirred at room temperature for 16 h, diluted with MeOH,filtered and purified by preparative HPLC (acetonitrile/water with 10 mMammonium acetate) to provide methyl((1S)-1-(((2S)-2-(6-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyridin-6-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyridin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(19.2 mg) as white solid and methyl((1S)-1-(((2R)-2-(6-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyridin-6-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyridin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(16.5 mg) as white solid (uncertain if pyrrolidine stereocenterracemized during this step or in a previous step). Resolution of2,6-bis(2-((S)-pyrrolidin-2-yl)-3H-imidazo[4,5-b]pyridin-6-yl)naphthaleneby chiral HPLC showed a broad peak, but individual diastereomers couldnot be resolved under the attempted conditions.

Analytical data for Example 22: LC-MS retention time 1.407 min; m/z815.60 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (500 MHz, MeOD) δ ppm 8.82-8.71 (m, 2H), 8.32-8.18 (m, 4H),8.14-8.07 (m, 2H), 7.92-7.84 (m, 2H), 5.37-5.29 (m, 2H), 4.30 (d, J=7.3Hz, 2H), 4.13-4.04 (m, 2H), 4.02-3.92 (m, 2H), 3.68 (s, 6H), 2.54-1.98(m, 10H), 1.03-0.89 (m, 12H).

Analytical data for Example 23: LC-MS retention time 1.442 min; m/z815.59 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (500 MHz, MeOD) δ ppm 8.89-8.66 (m, 2H), 8.36-8.20 (m, 4H),8.15-8.10 (m, 2H), 7.94-7.86 (m, 2H), 5.44-5.29 (m, 2H), 4.34 (d, J=7.6Hz, 1H), 4.30 (d, J=7.6 Hz, 1H), 4.21-3.80 (m, 4H), 3.74 (s, 3H), 3.68(s, 3H), 2.69-1.95 (m, 10H), 1.09-0.41 (m, 12H).

Example 24 Methyl((1S)-1-(((2S)-2-(5-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamateand Example 25A Methyl((1S)-1-(((2S)-2-(5-(6-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamateand Example 25B Methyl((1S)-1-(((2R)-2-(5-(6-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (63 mg, 0.17 mmol) was added to a stirred slurry of an HCl salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)naphthalene(45 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (29 mg,0.17 mmol) in DMF (1 mL) and DIPEA (0.12 mL, 0.69 mmol). The reactionmixture was stirred at room temperature for 16 h diluted with MeOH,filtered and purified by preparative HPLC (acetonitrile/water with 10 mMammonium acetate) to yield methyl((1S)-1-(((2S)-2-(5-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(11.2 mg) as yellow solid, methyl((1S)-1-(((2S)-2-(5-(6-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(17.3 mg) as yellow solid and methyl((1S)-1-(((2R)-2-(5-(6-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-naphthyl)-1H-imidazo[4,5-b]pyrazin-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(6.7 mg) as yellow solid (uncertain if pyrrolidine stereocenterracemized during this step or in a previous step). Resolution of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)naphthaleneby chiral HPLC showed a broad peak, but individual diastereomers couldnot be resolved under the attempted conditions.

Analytical data for Example 24: LC-MS retention time 1.420 min; m/z817.59 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (500 MHz, MeOD) δ ppm 9.14-9.06 (m, 2H), 8.71-8.64 (m, 2H),8.37-8.29 (m, 2H), 8.18-8.11 (m, 2H), 5.59-5.30 (m, 2H), 4.30 (d, J=7.3Hz, 2H), 4.13-3.96 (m, 4H), 3.78-3.64 (m, 6H), 2.57-2.01 (m, 10H),1.07-0.92 (m, 12H).

Analytical data for Example 25A: LC-MS retention time 1.507 min; m/z817.56 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.¹H NMR (500 MHz, MeOD) δ ppm 9.14-9.02 (m, 2H), 8.69-8.60 (m, 2H),8.36-8.27 (m, 2H), 8.15-8.08 (m, 2H), 5.41-5.36 (m, 1H), 5.34-5.29 (m,1H), 4.35 (d, J=7.9 Hz, 1H), 4.31 (d, J=7.3 Hz, 1H), 4.24-3.81 (m, 4H),3.78 (s, 3H), 3.68 (s, 3H), 2.62-1.97 (m, 10H), 1.09-0.46 (m, 12H).

Analytical data for Example 25B: LC-MS retention time 1.562 min; m/z817.58 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% acetonitrile/95% water/10 mM ammonium acetate andSolvent B was 5% water/95% acetonitrile/10 mM ammonium acetate. MS datawas determined using a MICROMASS® Platform for LC in electrospray mode.

Dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate

HATU (114 mg, 0.301 mmol) was added to a stirred solution of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalene (50mg), diisopropylethylamine (175 μL, 1.0 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (65mg, 0.30 mmol) in DMF (5 mL) and the resulting mixture was stirred atambient conditions for 2 hours. The reaction mixture was diluted withmethanol (2 mL) and water (2 mL). Then, the volatile component wasremoved in vacuo and the residue was purified by a reverse phase HPLC(water/acetonitrile/TFA) to provide a TFA salt of dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate(51.5 mg) as pale yellow solid. LC-MS retention time 1.117 min; m/z897.31 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min and an analysis time of 4 min whereSolvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFA salt 500MHz, MeOD) δ ppm 8.27 (br s, 2H), 8.10-8.18 (m, 4H), 8.01-8.07 (m, 2H),7.86-7.96 (m, 4H), 5.88-5.93 (m, 0.2H), 5.39 (t, J=7.0 Hz, 1.8H),4.33-4.38 (m, 2H), 4.12-4.22 (m, 2H), 3.89-4.05 (m, 7H), 3.70 (s, 6H),3.35-3.45 (m, 2H), 2.60-2.75 (m, 2H), 2.14-2.47 (m, 6.5H), 1.94-2.12 (m,2.5H), 1.32-1.69 (m, 8H).

Methyl((1S)-2-((2S)-2-(5-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (87 mg, 0.23 mmol) was added to a stirred solution of methyl((1S)-2-methyl-1-(((2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate(50 mg), diisopropylethylamine (133 μL, 0.76 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (50mg, 0.23 mmol) in DMF (3 mL) and the resulting mixture was stirred atambient conditions for 2 hours. The reaction mixture was diluted withmethanol (2 mL) and water (2 mL). Then the volatile component wasremoved in vacuo and the residue was purified by a reverse phase HPLC(water/acetonitrile/TFA) to provide a TFA salt of methyl((1S)-2-((2S)-2-(5-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(36 mg) as yellow solid. LC-MS retention time 1.177 min; m/z 855.30(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min,a hold time of 1 min and an analysis time of 4 min where Solvent A was10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500MHz, MeOD) δ ppm 8.22-8.30 (m, 1.8H), 8.20 (br s, 0.2H), 8.07-8.17 (m,4H), 8.00-8.06 (m, 1.8H), 7.98 (br s, 0.2H), 7.85-7.95 (m, 4H), 5.86 (m,0.1H), 5.35-5.44 (m, 1.8H), 5.25-5.31 (m, 0.1H), 4.36 (d, J=7.6 Hz,0.5H), 4.31 (d, J=6.7 Hz, 1H), 4.15 (br s, 1.5H), 3.87-4.05 (m, 4H),3.69 (br s, 6H), 3.34-3.47 (m, 1H), 2.96-3.23 (m, 2H), 2.61-2.77 (m,2.5H), 2.21-2.47 (m, 6H), 1.95-2.16 (m, 2H), 1.33-1.69 (m, 3.5H),1.00-1.05 (m, 0.3H), 0.94-0.99 (m, 3H), 0.91 (d, J=6.7 Hz, 2.7H).

Methyl((1S)-2-((2S)-2-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (36.6 mg, 0.096 mmol) was added to a stirred solution of a TFA saltof2-((S)-pyrrolidin-2-yl)-6-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazole(29 mg), diisopropylethylamine (56 μL, 0.32 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (21mg, 0.10 mmol) in DMF (2 mL) and the resulting mixture was stirred atambient conditions for 2 hours. The reaction mixture was diluted withmethanol (2 mL) and water (2 mL). Then the volatile component wasremoved in vacuo and the residue was purified by a reverse phase HPLC(water/acetonitrile/TFA) to provide a TFA salt of methyl((1S)-2((2S)-2-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(16.3 mg) as yellow solid. LC-MS retention time 1.023 min; m/z 847.31(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min,a hold time of 1 min and an analysis time of 4 min where Solvent A was10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500MHz, MeOD) δ ppm 8.29 (d, J=12.5 Hz, 2H), 8.15 (d, J=8.6 Hz, 1H), 8.10(d, J=8.5 Hz, 1H), 8.07 (s, 1H), 7.92-8.01 (m, 3H), 7.81-7.90 (m, 2H),5.37 (dd, J=7.9, 6.1 Hz, 1H), 5.30 (t, J=7.5 Hz, 1H), 4.28-4.39 (m, 2H),4.12-4.22 (m, 2H), 3.88-4.04 (m, 7H), 3.65-3.77 (m, 6H), 3.38-3.45 (m,1H), 2.56-2.69 (m, 2H), 2.20-2.40 (m, 6.5H), 2.01 (br s, 2.5H),1.57-1.69 (m, 2.5H), 1.35-1.53 (m, 6.5H).

Methyl((1S)-1-(((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (57.6 mg, 0.152 mmol) was added to a stirred solution of a TFA saltof2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole(47 mg), diisopropylethylamine (88 μL, 0.51 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (26.5 mg, 0.152 mmol)in DMF (4 mL) and the resulting mixture was stirred at ambientconditions for 2 hours. The reaction mixture was diluted with methanol(2 mL) and water (2 mL). The volatile component was removed in vacuo andthe residue was purified by a reverse phase HPLC (water/methanol/TFA),repurified by a reverse phase HPLC (water/acetonitrile/ammonium acetate)and finally repurified by a reverse phase HPLC (water/methanol/TFA) toprovide a TFA salt of methyl((1S)-1-(((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(33.3 mg) as yellow solid. LC-MS retention time 1.237 min; m/z 789.29(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min,a hold time of 1 min and an analysis time of 4 min where Solvent A was10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500MHz, MeOD) δ ppm 8.29 (d, J=8.9 Hz, 2H), 8.15 (d, J=8.5 Hz, 1H), 8.10(d, J=8.9 Hz, 1H), 7.95-8.03 (m, 4H), 7.93 (s, 1H), 7.84-7.91 (m, 3H),5.69-5.72 (m, 0.2H), 5.24-5.35 (m, 1.8H), 4.27 (dd, J=7.2, 2.6 Hz, 2H),4.09-4.19 (m, 2H), 3.85-3.97 (m, 2H), 3.67-3.76 (m, 6H), 2.55-2.68 (m,2H), 2.27-2.38 (m, 2H), 2.14-2.27 (m, 4H), 2.02-2.14 (m, 2H), 0.86-1.06(m, 12H).

Dimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate

HATU (54.6 mg, 0.144 mmol) was added to a stirred solution of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalene(25 mg), diisopropylethylamine (84 μL, 0.48 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(31.2 mg, 0.144 mmol) in DMF (5 mL) and the resulting mixture wasstirred at ambient conditions for 4 hours. The reaction mixture wasdiluted with methanol (2 mL) and water (2 mL). The volatile componentwas removed in vacuo and the residue was purified by a reverse phaseHPLC (water/methanol/TFA), repurified by a reverse phase HPLC(water/acetonitrile/ammonium acetate) and finally repurified by areverse phase HPLC (water/methanol/TFA) to provide a TFA salt ofdimethyl(2,6-naphthalenediylbis(1H-benzimidazole-5,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate(8.2 mg) as off-white solid. LC-MS retention time 1.220 min; m/z 461.3[½ M+H⁺]. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min and an analysis time of 4 min whereSolvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90%acetonitrile/10% water/0.1% TFA. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500MHz, MeOD) δ ppm 8.28 (br s, 2H), 8.07-8.18 (m, 4H), 8.00-8.07 (m, 2H),7.84-7.96 (m, 4H), 5.23-5.31 (m, 2H), 4.59-4.67 (m, 2H), 3.85-4.01 (m,6H), 3.70 (s, 6H), 3.28-3.44 (m, 4H), 2.71-2.80 (m, 2H), 2.58 (ddd,J=13.2, 6.5, 6.3 Hz, 2H), 2.03-2.20 (m, 4H), 1.41-1.65 (m, 8H), 1.13 (brs, 2H), 0.97 (br s, 2H).

Methyl((1S)-1-(((2S)-2-(4-((6-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (47.6 mg, 0.125 mmol) was added to a TFA salt of2,6-bis((2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)ethynyl)naphthalene(38 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (22 mg,0.13 mmol) in DMF (0.7 mL) and TEA (0.047 mL, 0.33 mmol) and the clearyellow solution was at rt ON. The reaction was diluted with MeOH (1 mL),filtered and purified by prep HPLC 15-100% MeOH/water/TFA buffer) toyield a TFA salt of methyl((1S)-1-(((2S)-2-(4-((6-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(37.1 mg) as light yellow solid. LC-MS retention time 2.530 min; m/z759.61 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-1-(((2S)-2-(4-((6-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

A TFA salt of4,4′-(2,6-naphthalenediyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole) (21mg, 0.025 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(12.9 mg) were dissolved into DMF (3 mL) and DIEA (0.043 mL, 0.246mmol). Then HATU (28.0 mg, 0.074 mmol) was added and the reactionmixture was stirred at room temperature for 2 h. The volatiles wereremoved under vacuum and the crude product was purified by prep HPLC(Waters Sunfire C18 column 30×100 mm 5 u eluted with a gradient of 0 to90% MeOH-Water+0.1% TFA) to yield a TFA salt of methyl((1S)-1-(((2S)-2-(4-((6-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(10.4 mg) as off white solid. LC-MS retention time 1.158 min; m/z 713.60(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 5 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.31 (s, 2H),8.11 (d, J=8.6 Hz, 2H), 7.94-8.03 (m, 2H), 7.84-7.94 (m, 2H), 5.29 (t,J=7.3 Hz, 2H), 4.26 (d, J=7.02 Hz, 2H), 4.14 (t, J=10.2 Hz, 2H),3.85-3.96 (m, 2H), 3.68 (s, 6H), 2.53-2.67 (m, 2H), 2.31 (d, J=10.4 Hz,2H), 2.16-2.28 (m, 4H), 2.03-2.15 (m, 2H), 0.88-1.08 (m, 12H).

Methyl((1S)-2-((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (120 mg, 0.316 mmol) was added to a stirred solution of a TFA saltof2-((2S)-2-pyrrolidinyl)-4-(4-(6-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(50 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(68.7 mg, 0.316 mmol) in DMF (5 mL) and DIEA (0.18 mL, 1.1 mmol) and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was diluted with MeOH (2 mL) and water (2 mL) and the volatileswere removed under vacuum. The residue was purified by prep HPLC (WatersSunfire C18 column 30×100 mm 5 u eluted with a gradient of 10 to 90%MeOH-Water+0.1% TFA) and then repurified by prep HPLC (Waters SunfireC18 column 30×150 mm 5 u eluted with a gradient of to % ACN-Water+0.1%TFA) to yield a TFA salt of methyl((1S)-2-((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(96 mg) as yellow solid. LC-MS retention time 1.207 min; m/z 873.63(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 5 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.29 (d, J=7.9Hz, 2H), 8.14 (d, J=8.9 Hz, 1H), 8.06-8.11 (m, 1H), 7.94-8.03 (m, 4H),7.90-7.94 (m, 1H), 7.80-7.90 (m, 3H), 5.74 (br s, 0.2H), 5.23-5.35 (m,1.8H), 4.32 (dd, J=8.1, 4.7 Hz, 2H), 4.16 (d, J=2.8 Hz, 2H), 3.94 (dd,J=9.5, 7.3 Hz, 6H), 3.69 (s, 6H), 3.31-3.48 (m, 4H), 2.55-2.68 (m, 2H),2.16-2.35 (m, 6H), 1.92-2.10 (m, 2H), 1.63 (d, J=12.8 Hz, 2H), 1.34-1.54(m, 6H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (57 mg, 0.150 mmol) was added to a stirred solution of(1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(25 mg, 0.050 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (33mg) in DMF (3 mL) and DIEA (0.078 mL, 0.50 mmol) and the reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas diluted with MeOH (2 mL) and water (2 mL) and the volatiles wereremoved under vacuum. The residue was purified by prep HPLC (WatersSunfire C18 column 30×100 mm 5 u eluted with a gradient of 10 to 100%MeOH-Water+0.1% TFA) to yield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(27 mg) as pale yellow solid. LC-MS retention time 1.280 min; m/z 897.65(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.28-8.32 (m,2H), 8.14 (d, J=8.6 Hz, 1H), 8.07-8.11 (m, 1H), 7.95-8.02 (m, 4H),7.84-7.93 (m, 4H), 5.12-5.23 (m, 2H), 4.62 (dd, J=7.6, 4.0 Hz, 2H),3.92-4.00 (m, 4H), 3.83-3.89 (m, 2H), 3.72-3.78 (m, 2H), 3.70 (s, 6H),3.35-3.46 (masked with methanol, m, 4H), 2.68-2.77 (m, 2H), 2.47-2.57(m, 2H), 2.00-2.15 (m, 4H), 1.42-1.65 (m, 6H), 1.06-1.17 (m, 2H),0.84-0.93 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (57 mg, 0.150 mmol) was added to a stirred solution of(1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(25 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (26 mg,0.15 mmol) in DMF (3 mL) and DIEA (0.070 mL, 0.40 mmol) and the reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas diluted with MeOH (2 mL) and water (2 mL) and the volatiles wereremoved under vacuum. The residue was purified by prep HPLC (WatersSunfire C18 column 30×100 mm 5 u eluted with a gradient of 10 to 100%MeOH-Water+0.1% TFA) to yield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(34.8 mg) as pale yellow solid. LC-MS retention time 1.402 min; m/z813.69 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.29 (d,J=7.9 Hz, 2H), 8.14 (d, J=8.9 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.95-8.01(m, 4H), 7.92 (s, 1H), 7.84-7.90 (m, 3H), 5.16 (ddd, J=11.6, 9.2, 7.0Hz, 2H), 4.58 (dd, J=6.4, 2.1 Hz, 2H), 3.81-3.88 (m, 2H), 3.66-3.75 (m,6H), 2.67-2.77 (m, 2H), 2.46-2.57 (m, 2H), 2.21 (dq, J=12.9, 6.5 Hz,2H), 2.06-2.14 (m, 2H), 1.08-1.18 (m, 2H), 1.04 (d, J=6.7 Hz, 6H), 0.95(d, J=6.7 Hz, 6H), 0.91 (br s, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-quinolinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (32.7 mg, 0.086 mmol) was added to a solution of a hydrochloridesalt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoline(25 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (15 mg,0.086 mmol) in DMF (1 mL) and DIPEA (0.059 mL, 0.34 mmol) and themixture was stirred at rt for 16 h. The reaction was diluted with MeOH,and purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield a TFAsalt of dimethyl(2S,2′S)-1,1′-((1R,1′R,3S,3′S,5R,5′R)-3,3′-(6,6′-(quinoline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(8.3 mg) as a yellow solid. LC-MS retention time 1.88 min; m/z 838[M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water: 10%methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.64-8.80 (1H, m),8.49-8.62 (1H, m), 7.45-8.48 (9H, m), 5.21-5.52 (2H, m), 4.50-4.68 (2H,m), 3.82-4.13 (2H, m), 3.70-3.79 (2H, m), 3.68, 3.66 (6H, s, s),2.48-2.83 (3H, m), 2.02-2.28 (3H, m), 1.09-1.30 (2H, m), 0.83-1.08 (14H,m).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-quinoxalinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (25 mg, 0.066 mmol) was added to a solution of a TFA salt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxaline(28 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (11.5 mg,0.066 mmol) in DMF (0.5 mL) and DIPEA (0.045 mL, 0.26 mmol) and themixture was stirred at rt for 2 h. The reaction was diluted with MeOH,and purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield a TFAsalt of dimethyl(2S,2′S)-1,1′-((1R,1′R,3S,3′S,5R,5′R)-3,3′-(6,6′-(quinoxaline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(27 mg) as a yellow solid. LC-MS retention time 1.94 min; m/z 839[M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (TFA salt, 400 MHz, MeOD) δ ppm 9.56 (s, 1H),8.67 (s, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J=8.8 Hz,1H), 8.24 (d, J=8.8 Hz, 1H), 8.17 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.93(d, J=8.5 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 5.30 (app dd, J=9.0, 6.8 Hz,2H), 4.60 (app d, J=6.0 Hz, 2H), 3.93-3.84 (m, 2H), 3.68 (s, 6H),2.80-2.70 (m, 2H), 2.63-2.51 (m, 2H), 2.29-2.09 (m, 4H), 1.21-1.11 (m,2H), 1.03 (d, J=6.8 Hz, 6H), 1.00-0.90 (m, 2H), 0.93 (d, J=6.5 Hz, 6H).

Dimethyl(2,6-quinoxalinediylbis(1H-benzimidazole-5,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate

HATU (25.9 mg, 0.068 mmol) was added to a solution of a TFA salt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxaline(29 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(14.8 mg, 0.068 mmol) in DMF (0.5 mL) and DIPEA (0.046 mL, 0.27 mmol)and the mixture was stirred at rt for 16 h. The reaction was dilutedwith MeOH, and purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield a TFA salt of dimethyl(1S,1′S)-2,2′-((1R,1′R,3S,3′S,5R,5′R)-3,3′-(6,6′-(quinoxaline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl)dicarbamate(32.5 mg) as a yellow solid. LC-MS retention time 1.74 min; m/z 462 [½M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (TFA salt, 400 MHz, MeOD) δ ppm 9.53 (s, 1H),8.70 (s, 1H), 8.55 (dd, J=8.8, 1.5 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.31(d, J=8.8 Hz, 1H), 8.27 (dd, J=8.8, 1.8 Hz, 1H), 8.19 (br s, 1H), 8.08(dd, J=8.8, 1.5 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H),5.28 (app dd, J=8.8, 6.8 Hz, 2H), 4.63 (app d, J=7.3 Hz, 2H), 3.99-3.86(m, 6H), 3.69 (s, 6H), 3.44-3.29 (m, 4H), 2.81-2.71 (m, 2H), 2.63-2.52(m, 2H), 2.20-2.03 (m, 4H), 1.68-1.37 (m, 8H), 1.17-1.08 (m, 2H),0.99-0.92 (m, 2H).

Dimethyl(2,6-quinolinediylbis(1H-benzimidazole-5,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate

HATU (34.0 mg, 0.089 mmol) was added to a solution of a hydrochloridesalt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoline(26 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(19.4 mg, 0.089 mmol) in DMF (0.5 mL) and DIPEA (0.061 mL, 0.350 mmol)and the mixture was stirred at rt for 16 h. The reaction was dilutedwith MeOH and purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield a TFA salt of dimethyl(1S,1′S)-2,2′-((1R,1′R,3S,3′S,5R,5′R)-3,3′-(6,6′-(quinoline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl)dicarbamate(6.0 mg) as a yellow solid. LC-MS retention time 1.65 min; m/z 462 [½M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.70 (1H, d, J=8.5 Hz),8.57 (1H, s), 8.23-8.45 (5H, m), 8.17 (1H, s), 8.01-8.12 (1H, m),7.88-7.97 (2H, m), 5.27 (2H, t, J=7.8 Hz), 4.33-4.68 (2H, m), 3.84-4.02(6H, m), 3.69 (6H, s), 3.35-3.47 (4H, m), 2.67-2.81 (2H, m), 2.49-2.64(2H, m), 1.91-2.21 (4H, m), 1.35-1.71 (8H, m), 1.07-1.17 (2H, m),0.85-1.00 (2H, m).

Methyl((1S)-2-((2S)-2-(4-chloro-5-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (45 mg, 0.118 mmol) was added to a solution of4-chloro-2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole(20 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(25.6 mg, 0.118 mmol) in DMF (3 mL) and DIEA (0.070 mL, 0.40 mmol) andthe reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with MeOH (2 mL) and water (2 mL) and thevolatiles were removed under vacuum. The residue was purified by prepHPLC (Waters Sunfire C18 column 30×100 mm 5 u eluted with a gradient of10 to 100% MeOH-Water+0.1% TFA) and then repurified by HPLC (WatersSunfire C18 column 30×150 mm 5 u eluted with a gradient of 10 to 100%ACN-Water+0.1% TFA) to yield a TFA salt of methyl((1S)-2-((2S)-2-(4-chloro-5-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(12.9 mg) as yellow solid. LC-MS retention time 1.595 min; m/z 907.39(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.20-8.28 (m,2H), 8.09-8.12 (m, 1H), 8.02-8.08 (m, 1H), 7.91-8.00 (m, 3H), 7.87-7.91(m, 2H), 7.80-7.87 (m, 2H), 5.28 (t, J=7.5 Hz, 1H), 5.06-5.14 (m, 1H),4.25-4.35 (m, 2H), 4.11-4.19 (m, 1H), 4.00-4.07 (m, 1H), 3.85-4.00 (m,6H), 3.63-3.69 (m, 6H), 3.32-3.43 (m, 4H), 2.57-2.64 (m, 1H), 2.34-2.40(m, 1H), 2.26-2.32 (m, 2H), 2.12-2.25 (m, 4H), 1.95-2.09 (m, 2H),1.34-1.64 (m, 8H).

Methyl((1S)-1-(((2S)-2-(4-(6-(4-(4-chloro-2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (45 mg, 0.118 mmol) was added to a solution of4-chloro-2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole(20 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (20.7 mg,0.118 mmol) in DMF (3 mL) and DIEA (0.070 mL, 0.40 mmol) and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was diluted with MeOH (2 mL) and water (2 mL) and the volatileswere removed under vacuum. The residue was purified by prep HPLC (WatersSunfire C18 column 30×100 mm 5 u eluted with a gradient of 10 to 100%MeOH-Water+0.1% TFA) and then repurified by HPLC (Waters Sunfire C18column 30×150 mm 5 u eluted with a gradient of 10 to 100% ACN-Water+0.1%TFA) to yield a TFA salt of methyl((1S)-1-(425)-2-(4-(6-(4-(4-chloro-2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(3.6 mg) as yellow solid. LC-MS retention time 1.715 min; m/z 823.49(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.24-8.29 (m,1H), 8.22 (s, 1H), 8.08-8.15 (m, 1H), 8.03-8.08 (m, 1H), 7.81-8.01 (m,7H), 5.31 (t, J=7.5 Hz, 1H), 5.12 (app t, J=7.5 Hz, 1H), 4.21-4.32 (m,2H), 4.08-4.19 (m, 1H), 3.99-4.08 (m, 1H), 3.85-3.96 (m, 2H), 3.57-3.74(m, 6H), 2.56-2.67 (m, 1H), 2.35-2.46 (m, 1H), 2.28-2.35 (m, 2H),2.20-2.26 (m, 2H), 2.05-2.19 (m, 4H), 0.90-1.09 (m, 12H).

Methyl((1S)-2-((1R,3S,5R)-3-(7-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (103 mg, 0.271 mmol) was added to a solution of2-((S)-pyrrolidin-2-yl)-7-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazole(45 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(58.8 mg, 0.271 mmol) in DMF (3 mL) and DIEA (0.16 mL, 0.90 mmol) andthe reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with MeOH (2 mL) and water (2 mL) and thevolatiles were removed under vacuum. The residue was purified by prepHPLC (Waters Sunfire C18 column 30×100 mm 5 u eluted with a gradient of10 to 100% MeOH-Water+0.1% TFA) and then repurified by HPLC (WatersSunfire C18 column 30×150 mm 5 u eluted with a gradient of 0 to 90%ACN-Water+0.1% TFA) to yield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(7-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(8.7 mg) as white solid. LC-MS retention time 1.307 min; m/z 897.67(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.51-8.57 (m,2H), 8.40 (s, 1H), 8.30 (s, 1H), 8.23 (d, J=10.1 Hz, 1H), 8.18 (d, J=8.6Hz, 1H), 8.05-8.15 (m, 3H), 8.00 (s, 1H), 7.87 (dd, J=8.6, 1.8 Hz, 1H),7.79-7.85 (m, 1H), 5.43 (t, J=7.3 Hz, 1H), 5.30 (t, J=7.3 Hz, 1H),4.28-4.40 (m, 2H), 4.19 (br s, 2H), 3.88-4.07 (m, 6H), 3.70 (d, J=1.5Hz, 6H), 3.26-3.45 (overlap with methanol, m, 4H), 2.57-2.71 (m, 2H),2.30-2.42 (m, 3H), 2.20-2.29 (m, 3H), 1.93-2.10 (m, 2H), 1.58-1.68 (m.,2H), 1.34-1.58 (m, 6H).

Methyl((1S)-2-((1R,3S,5R)-3-(7-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (24.5 mg, 0.065 mmol) was added to a solution of a TFA salt of2,6-bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)quinoline (30mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (11.3 mg,0.065 mmol) in DMF (1 mL) and DIPEA (0.044 mL, 0.252 mmol) and themixture was stirred at rt for 2 h. The reaction was diluted with MeOHand purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield a TFAsalt of dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(6,6′-(quinoline-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(34 mg) as a yellow solid. LC-MS retention time 1.82 min; m/z 814[M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.71 (1H, d, J=8.8 Hz),8.57 (1H, s), 8.21-8.43 (5H, m), 8.18 (1H, s), 8.04 (1H, dd, J=8.5, 1.5Hz), 7.88-7.96 (2H, m), 5.40 (2H, t, J=7.03 Hz), 4.31 (2H, d, J=6.8 Hz),4.09-4.21 (2H, m), 3.91-4.06 (2H, m), 3.68 (6H, s), 2.58-2.73 (2H, m),2.20-2.49 (6H, m), 2.02-2.19 (2H, m), 0.96 (6H, dd, J=6.8, 1.8 Hz), 0.90(6H, dd, J=6.7, 1.6 Hz).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (82 mg, 0.22 mmol) was added to a solution of6-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazole(34 mg), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (37.8 mg,0.216 mmol) and DIEA (0.13 mL, 0.72 mmol) in DMF (3 mL) and the reactionwas stirred 2 h at room temperature. The reaction mixture was dilutedwith MeOH (2 ml) and water (2 mL). The volatiles were removed undervacuum. The residue was purified by prep HPLC (Waters Sunfire C18 column30×150 mm 5 u eluted with a gradient of 10 to 80% ACN-Water+0.1% TFA) toafford a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(49.8 mg) as pale yellow solid. LC-MS retention time 1.357 min; m/z787.65 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.29 (d,J=10.7 Hz, 2H), 8.07-8.19 (m, 3H), 7.94-8.05 (m, 3H), 7.84-7.92 (m, 2H),5.29 (dd, J=9.2, 6.7 Hz, 1H), 5.18 (dd, J=9.2, 7.0 Hz, 1H), 4.59 (dd,J=12.4, 6.6 Hz, 2H), 3.81-3.91 (m, 2H), 3.69 (s, 6H), 2.67-2.80 (m, 2H),2.48-2.61 (m, 2H), 2.07-2.27 (m, 4H), 1.09-1.19 (m, 2H), 0.99-1.06 (m,6H), 0.88-1.00 (m, 8H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (82 mg, 0.216 mmol) was added to a solution of6-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazole(34 mg), (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)aceticacid (46.9 mg, 0.216 mmol) and DIEA (0.13 mL, 0.72 mmol) in DMF (3 mL)and the reaction was stirred for 2 h at room temperature. The reactionmixture was diluted with MeOH (2 ml) and water (2 mL). The volatileswere removed under vacuum. The residue was purified by prep HPLC (WatersSunfire C18 column 30×150 mm 5 u eluted with a gradient of 10 to 80%ACN-Water+0.1% TFA) to afford a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(38 mg) as pale yellow solid. LC-MS retention time 1.240 min; m/z 871.66(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.30 (d, J=6.1Hz, 2H), 8.08-8.18 (m, 3H), 8.04 (dd, J=8.6, 1.5 Hz, 1H), 7.95-8.01 (m,2H), 7.85-7.92 (m, 2H), 5.27 (dd, J=9.2, 6.7 Hz, 1H), 5.16 (dd, J=9.2,7.0 Hz, 1H), 4.59-4.66 (m, 2H), 3.84-4.01 (m, 6H), 3.70 (s, 6H),3.35-3.45 (m, 4H), 2.69-2.80 (m, 2H), 2.48-2.61 (m, 2H), 2.03-2.20 (m,4H), 1.57-1.65 (m, 2H), 1.40-1.56 (m, 6H), 1.07-1.17 (m, 2H), 0.97 (brs, 1H), 0.91 (br s, 1H).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6′-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2,2′-binaphthalen-6-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (22.7 mg, 0.060 mmol) was added to a solution of a TFA salt of6,6′-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-5-yl)-2,2′-binaphthyl(22 mg), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (10.5 mg,0.060 mmol) and DIEA (0.035 mL, 0.20 mmol) in DMF (3 mL) and thereaction was stirred at rt for 2 h. The reaction mixture was dilutedwith MeOH (2 ml) and water (2 mL) and the volatiles were removed undervacuum. The residue was purified by prep HPLC (Waters Sunfire C18 column30×100 mm 5 u eluted with a gradient of 10 to 80% MeOH-Water+0.1% TFA)to afford a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(5-(6′-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2,2′-binaphthalen-6-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(15.6 mg) as tan solid. LC-MS retention time 1.765 min; m/z 482.68 (½M+H+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.36 (s, 2H),8.27 (s, 2H), 8.12-8.18 (m, 4H), 8.11 (s, 2H), 8.05 (app t, J=8.6 Hz,4H), 7.91-7.96 (m, 2H), 7.86-7.91 (m, 2H), 5.29 (dd, J=9.2, 6.7 Hz, 2H),4.61 (d, J=6.4 Hz, 2H), 3.85-3.91 (m, 2H), 3.70 (s, 6H), 2.72-2.80 (m,2H), 2.53-2.62 (m, 2H), 2.12-2.26 (m, 4H), 1.13-1.21 (m, 2H), 1.04 (d,J=6.7 Hz, 6H), 0.99 (br s, 2H), 0.95 (d, J=6.7 Hz, 6H).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-1,5-naphthyridin-2-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (8.7 mg, 0.023 mmol) was added to a solution of a TFA salt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridine(12 mg, 9.93 μmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (4.2 mg) in DMF (0.5 mL) and DIPEA (0.017 mL, 0.099 mmol) and themixture was stirred at rt for 16 h. The reaction was diluted with MeOH,and purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield a TFAsalt of dimethyl(2S,2′S)-1,1′-((1R,1′R,3S,3′S,5R,5′R)-3,3′-(6,6′-(1,5-naphthyridine-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(5.6 mg) as yellow solid. LC-MS retention time 1.91 min; m/z 420 [½M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.59-8.67 (4H, m), 8.48(2H, dd, J=8.8, 1.3 Hz), 8.44 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=8.5 Hz),5.29 (2H, dd, J=9.2, 6.7 Hz), 4.60 (2H, d, J=6.5 Hz), 3.84-3.92 (2H, m),3.68 (6H, s), 2.69-2.80 (2H, m), 2.51-2.62 (2H, m), 2.07-2.27 (4H, m),1.10-1.21 (2H, m), 1.02 (6H, d, J=6.8 Hz), 0.95-1.00 (2H, m), 0.93 (6H,d, J=6.8 Hz).

Dimethyl(1,5-naphthyridine-2,6-diylbis(1H-benzimidazole-5,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate

HATU (8.68 mg, 0.023 mmol) was added to a solution of a TFA salt of2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridine(12 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(5.0 mg, 0.023 mmol) in DMF (0.5 mL) and DIPEA (0.016 mL, 0.089 mmol)and the mixture was stirred at rt for 3 h. The reaction was diluted withMeOH and purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yielda TFA salt of dimethyl(1S,1′S)-2,2′-((1R,1′R,3S,3′S,5R,5′R)-3,3′-(6,6′-(1,5-naphthyridine-2,6-diyl)bis(1H-benzo[d]imidazole-6,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl)dicarbamate(11 mg) as yellow solid. LC-MS retention time 1.73 min; m/z 462 [½M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 8.61-8.68 (4H, m), 8.50(2H, dd, J=8.8, 1.51 Hz), 8.45 (2H, d, J=8.8 Hz), 7.93 (2H, d, J=8.8Hz), 5.28 (2H, dd, J=9.3, 6.8 Hz), 4.64 (2H, d, J=7.5 Hz), 3.84-4.02(6H, m), 3.69 (6H, s), 3.35-3.46 (4H, m), 2.75 (2H, dd, J=13.7, 9.2 Hz),2.58 (2H, d, J=6.8 Hz), 1.99-2.22 (4H, m), 1.36-1.69 (8H, m), 1.07-1.19(2H, m), 0.96 (2H, m).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (76 mg, 0.20 mmol) was added to a solution of2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-4-chloro-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazole(34 mg), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (35.2 mg,0.201 mmol) and DIEA (0.12 mL, 0.67 mmol) in DMF (3 mL) and theresulting mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with methanol (2 mL) and water (2 mL) andthe volatile component was removed in vacuo. The residue was purified bya reverse phase preparative HPLC (water/methanol, 0.1% TFA) to yield aTFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(41.3 mg) as yellow solid. LC-MS retention time 1.717 min; m/z 821.58(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire C18 4.6×30 mm 5 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.24(d, J=1.8 Hz, 2H), 8.01-8.13 (m, 4H), 7.84-7.98 (m, 3H), 5.29 (dd,J=9.2, 6.7 Hz, 1H), 5.09 (t, J=7.2 Hz, 1H), 4.60 (t, J=7.2 Hz, 2H),3.86-3.91 (m, 1H), 3.71-3.76 (m, 1H), 3.69 (s, 3H), 3.68 (m, 3H), 2.77(dd, J=13.6, 9.3 Hz, 1H), 2.57 (ddd, J=13.6, 6.7, 6.6 Hz, 1H), 2.44-2.53(m, 2H), 2.11-2.26 (m, 3H), 1.99-2.10 (m, 1H), 1.10-1.22 (m, 2H),0.89-1.09 (m, 13H), 0.80-0.84 (m, 1H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (45.0 mg, 0.118 mmol) was added to a solution of2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-4-chloro-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazole(20 mg, 0.039 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(25.7 mg) and DIEA (0.069 mL, 0.39 mmol) in DMF (3 mL) and the resultingmixture was stirred at ambient temperature for 2 hours. The reactionmixture was diluted with methanol (2 mL) and water (2 mL) and thevolatile component was removed in vacuo. The residue was purified by areverse phase preparative HPLC (water/methanol, 0.1% TFA) to yield a TFAsalt of methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(28.1 mg) as pale yellow solid. LC-MS retention time 1.597 min; m/z905.67 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire C18 4.6×30 mm 5 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10%water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.24(s, 2H), 8.02-8.13 (m, 4H), 7.86-7.97 (m, 3H), 5.27 (dd, J=9.2, 7.0 Hz,1H), 5.08 (t, J=7.2 Hz, 1H), 4.65 (t, J=7.3 Hz, 2H), 3.88-4.02 (m, 5H),3.75-3.83 (m, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.36-3.49 (m, 4H), 2.77(dd, J=13.7, 9.5 Hz, 1H), 2.57 (ddd, J=13.7, 6.7, 6.4 Hz, 1H), 2.46-2.53(m, 2H), 2.00-2.20 (m, 4H), 1.55-1.69 (m, 4H), 1.40-1.70 (m, 4H),1.08-1.20 (m, 2H), 0.94-1.00 (m, 1H), 0.80-0.84 (m, 1H).

Methyl((1S)-1-(((1S,3R,5S)-3-(4-(6-(3-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (47.8 mg, 0.126 mmol) was added to a mixture of a TFA salt of(1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(40 mg), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (22 mg, 0.13mmol) and DIEA (0.073 mL, 0.42 mmol) in DMF (3 mL) and the resultingmixture was stirred at ambient temperature for 2 hours. The reactionmixture was diluted with methanol (2 mL) and water (2 mL) and thevolatile component was removed in vacuo. The residue was partiallypurified by a reverse phase HPLC (water/methanol, 0.1% TFA) and thenrepurified by reverse phase HPLC (water/acetonitrile, 0.1% TFA) to yielda TFA salt of methyl((1S)-1-(((1S,3R,5S)-3-(4-(6-(3-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(45 mg) as a white solid. LC-MS retention time 1.458 min; m/z 813.30(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% methanol/90% water/10 mM ammonium acetate and Solvent B was 10%water/90% methanol/10 mM ammonium acetate. MS data was determined usinga MICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz,MeOD) δ ppm 8.30 (d, J=4.6 Hz, 2H), 8.18 (s, 1H), 8.14 (d, J=8.9 Hz,1H), 8.10 (d, J=8.9 Hz, 1H), 7.98-8.02 (m, 2H), 7.98 (s, 1H), 7.93 (d,J=8.2 Hz, 1H), 7.88 (dd, J=8.7, 1.7 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H),7.69 (t, J=7.8 Hz, 1H), 5.13-5.20 (m, 2H), 4.57 (t, J=6.1 Hz, 2H),3.80-3.88 (m, 2H), 3.69 (d, J=6.1 Hz, 6H), 2.67-2.77 (m, 2H), 2.51 (dq,J=13.7, 6.8 Hz, 2H), 2.15-2.25 (m, 2H), 2.10 (dq, J=13.8, 6.8 Hz, 2H),1.08-1.18 (m, 2H), 1.03 (dd, J=6.7, 4.6 Hz, 6H), 0.95 (dd, J=6.7, 3.4Hz, 6H), 0.92 (dd, J=5.3, 2.0 Hz, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-6-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (13.16 mg, 0.035 mmol) was added to a solution of a TFA salt of2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline(14 mg, 0.015 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (6.1 mg) in DMF (0.5 mL) and DIPEA (0.024 mL, 0.135 mmol) and themixture was stirred at rt for 16 h. The reaction was diluted with MeOHand purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield a TFAsalt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-6-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(11.8 mg,) as a yellow solid. LC-MS retention time 1.77 min; m/z 789[M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 9.59 (s, 1H), 8.67 (s,1H), 8.51 (d, J=8.8 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.27 (d, J=8.8 Hz,1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 8.11 (s, 1H), 7.92 (d, J=8.5 Hz, 1H),5.29 (dd, J=9.2, 6.7 Hz, 1H), 5.17 (dd, J=9.2, 7.2 Hz, 1H), 4.58 (dd,J=13.2, 6.7 Hz, 2H), 3.78-3.92 (m, 2H), 3.68 (s, 6H), 2.67-2.79 (m, 2H),2.45-2.62 (m, 2H), 2.03-2.27 (m, 4H), 1.07-1.21 (m, 2H), 1.03 (d, J=6.8Hz, 6H), 0.93-1.00 (m, 2H), 0.93 (dd, J=6.3, 5.8 Hz, 6H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-6-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (15.0 mg, 0.040 mmol) was added to a solution of a TFA salt of2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline(16 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(8.6 mg, 0.040 mmol) in DMF (0.5 mL) and DIPEA (0.027 mL, 0.16 mmol) andthe mixture was stirred at rt for 16 h. The reaction was diluted withMeOH, and purified by prep HPLC (H₂O-MeOH with 10 mM NH₄OAc buffer) toyield methyl((1S)-2-((1R,3S,5R)-3-(4-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-6-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(14.5 mg) as yellow solid. LC-MS retention time 1.58 min; m/z 873[M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10%methanol: 0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. FlowRate=4 mL/min. Start B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 9.34 (s, 1H), 8.36 (s,1H), 8.28 (d, J=1.0 Hz, 1H), 8.08-8.19 (m, 2H), 8.03 (d, J=8.8 Hz, 1H),7.66 (d, J=8.5 Hz, 1H), 7.54 (s, 1H), 5.27 (t, J=6.9 Hz, 1H), 5.18 (dd,J=8.9, 4.9 Hz, 1H), 4.69 (d, J=5.5 Hz, 2H), 3.87-4.03 (m, 4H), 3.73-3.85(m, 2H), 3.68 (s, 6H), 3.32-3.47 (m, 4H), 2.50-2.61 (m, 3H), 2.40-2.49(m, 1H), 1.99-2.16 (m, 4H), 1.51-1.72 (m, 6H), 1.38-1.51 (m, 2H),1.09-1.22 (m, 2H), 0.76-0.92 (m, 2H).

Methyl((1S)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (157 mg, 0.413 mmol) was added to a solution of methyl(S)-1-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(130 mg),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (90mg, 0.41 mmol) and DIEA (0.36 mL, 2.1 mmol) in DMF (4 mL) and thereaction was stirred 2 h at room temperature. The reaction mixture wasdiluted with MeOH (2 mL) and water (2 mL). The volatiles were removedunder vacuum. The material was purified on reverse phase HPLC(water/methanol, 0.1% TFA) to afford a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(194 mg) as yellow solid. LC-MS retention time 1.307 min; m/z 829.27(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 4 mL/min, a gradient of 100% SolventA/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where Solvent A was10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90%methanol/0.1% TFA. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.31(s, 1H), 8.29 (s, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H),8.11 (d, J=8.9 Hz, 1H), 8.02 (dd, J=8.5, 1.5 Hz, 1H), 8.00 (s, 1H), 7.98(dd, J=8.5, 1.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.88 (dd, J=8.5, 1.8Hz, 1H), 5.27 (dd, J=9.2, 6.7 Hz, 1H), 5.18 (dd, J=9.2, 7.0 Hz, 1H),4.62-4.67 (m, 1H), 4.58 (d, J=6.4 Hz, 1H), 3.87-4.01 (m, 3H), 3.82-3.87(m, 1H), 3.70 (m, 6H), 3.36-3.44 (m, 2H), 2.74 (td, J=13.3, 9.5 Hz, 2H),2.48-2.62 (m, 2H), 2.04-2.24 (m, 4H), 1.40-1.60 (m, 4H), 1.09-1.19 (m,2H), 1.04 (d, J=6.7 Hz, 3H), 0.89-0.99 (m, 5H).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (100 mg, 0.263 mmol) was added to a solution of methyl(S)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate(118 mg), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (46.2 mg,0.263 mmol) and DIEA (0.31 mL, 1.8 mmol) in DMF (4 mL) and the reactionwas stirred 2 h at room temperature. The reaction mixture was dilutedwith MeOH (2 mL) and water (2 mL). The volatiles were removed undervacuum using a rotavap and the residue was purified on reverse phaseHPLC (water/methanol, 0.1% TFA) to afford the a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(55.3 mg). LC-MS retention time 1.320 min; m/z 829.42 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector ata detector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where Solvent A was 10% methanol/90%water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.31 (s, 1H) 8.29 (s, 1H),8.08-8.18 (m, 3H), 8.04 (dd, J=8.9, 1.5 Hz, 1H), 7.95-8.00 (m, 2H), 7.90(d, J=8.6 Hz, 1H), 7.87 (dd, J=8.6, 1.8 Hz, 1H), 5.29 (dd, J=9.3, 6.9Hz, 1H), 5.17 (dd, J=9.2, 7.0 Hz, 1H), 4.62 (dd, J=9.2, 7.3 Hz, 2H),3.96 (td, J=10.8, 2.9 Hz, 2H), 3.83-3.92 (m, 2H), 3.64-3.77 (m, 6H),3.35-3.46 (m, 2H), 2.74 (ddd, J=19.3, 13.5, 9.3 Hz, 2H), 2.48-2.62 (m,2H), 2.06-2.26 (m, 4H), 1.45-1.63 (m, 4H), 1.06-1.22 (m, 2H), 1.03 (d,J=6.7 Hz, 3H), 0.96-1.01 (m, 1H), 0.93 (d, J=6.7 Hz, 3H), 0.88-091 (m,1H).

Methyl((1S)-2-((1R,3S,5R)-3-(5-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

NCS (14.98 mg, 0.112 mmol) was added to a solution of methyl((1S)-2-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(93 mg) in DMF and the reaction mixture was heated at 50° C. (oil bathtemp) for 2 h. The crude reaction mixture was purified on reverse phaseHPLC (water/methanol, 0.1% TFA) to afford a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(5-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(102.8 mg). LC-MS retention time 1.648 min; m/z 863.32 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector ata detector wave length of 220 nM. The elution conditions employed a flowrate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where Solvent A was 10% methanol/90%water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.22 (br s, 2H), 8.10 (s,1H), 8.00-8.06 (m, 3H), 7.85-7.94 (m, 3H), 5.28 (dd, J=9.2, 7.0 Hz, 1H),5.09 (t, J=7.2 Hz, 1H), 4.65 (d, J=7.3 Hz, 1H), 4.59 (d, J=7.0 Hz, 1H),3.89-3.99 (m, 3H), 3.66-3.77 (m, 7H), 3.35-3.44 (m, 2H), 2.77 (dd,J=13.6, 9.3 Hz, 1H), 2.57 (ddd, J=13.8, 6.8, 6.6 Hz, 1H), 2.47-2.52 (m,2H), 2.02-2.22 (m, 4H), 1.44-1.63 (m, 4H), 1.13 (dt, J=8.6, 5.8 Hz, 2H),1.05 (d, J=7.0 Hz, 3H), 0.92-1.02 (m, 4H), 0.83 (d, J=1.8 Hz, 1H).

Methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

NCS (10.31 mg, 0.077 mmol) was added to a solution of methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(64 mg) in DMF (2 mL) and the reaction mixture was heated at 50° C. for2 h. The crude reaction mixture was purified on reverse phase HPLC(water/methanol, 0.1% TFA) and repurified on reverse phase HPLC(water/ACN, 0.1% TFA) to afford the TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(5-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(44.7 mg) as tan solid. LC-MS retention time 1.63 min; m/z 863.39 (MH+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90%methanol/0.1% TFA. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.24(br s, 2H), 8.02-8.12 (m, 4H), 7.86-7.95 (m, 3H), 5.28 (dd, J=9.2, 6.7Hz, 1H), 5.08 (t apparent, J=7.0 Hz, 1H), 4.65 (d, J=7.6 Hz, 1H), 4.60(d, J=6.7 Hz, 1H), 3.93-4.01 (m, 2H), 3.86-3.91 (m, 1H), 3.75-3.81 (m,1H), 3.65-3.74 (m, 6H), 3.36-3.46 (m, 2H), 2.77 (dd, J=13.7, 9.2 Hz,1H), 2.57 (ddd, J=13.7, 6.7, 6.4 Hz, 1H), 2.49 (dd, J=7.8, 3.2 Hz, 2H),2.12-2.25 (m, 2H), 2.00-2.12 (m, 2H), 1.54-1.67 (m, 3H), 1.41-1.51 (m,1H), 1.09-1.19 (m, 2H), 0.97-1.06 (m, 4H), 0.94 (d, J=6.7 Hz, 3H), 0.82(br s, 1H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (5.64 mg, 0.015 mmol) was added to a solution of a TFA salt of6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline(6.0 mg) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(3.2 mg) in DMF (0.5 mL) and DIPEA (10.13 μL, 0.058 mmol) and themixture was stirred at rt for 16 h. The solvent was removed and theresidue was purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(5.5 mg) as a yellow solid. LC-MS retention time 1.60 min; m/z 873[M+H]⁺. (Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=95% water/5%methanol/10 mM ammonium acetate. Solvent B=5% water/95% methanol/10 mMammonium acetate. Flow Rate=4 mL/min. Start % B=0. Final % B=100.Gradient Time=2 min. Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 9.42(s, 1H), 8.41-8.50 (m, 2H), 8.30 (d, J=1.3 Hz, 2H), 8.19 (d, J=1.0 Hz,1H), 8.07 (dd, J=8.5, 1.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 5.13-5.33 (m,3H), 4.57-4.70 (m, 1H), 3.81-4.04 (m, 6H), 3.62-3.77 (m, 6H), 3.34-3.46(m, 4H), 2.65-2.82 (m, 2H), 2.45-2.61 (m, 2H), 2.01-2.22 (m, 4H),1.40-1.65 (m, 8H), 1.03-1.17 (m, 2H), 0.83-0.98 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (5.64 mg, 0.015 mmol) was added to a solution of a TFA salt of6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline(6.0 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (2.60mg, 0.015 mmol) in DMF (0.5 mL) and DIPEA (10.13 μL, 0.058 mmol) and themixture was stirred at rt for 16 h. The solvent was removed and theresidue was purified by prep HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(3.6 mg) as yellow solid. LC-MS retention time 1.75 min; m/z 789 [M+H]⁺.(Column PHENOMENEX® Luna3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol: 0.1% TFA. Flow Rate=4mL/min. Start % B=0. Final % B=100. Gradient Time=3 min.Wavelength=220). ¹H NMR (400 MHz, MeOD) δ ppm 9.42 (s, 1H), 8.41-8.48(m, 2H), 8.30 (d, J=1.3 Hz, 2H), 8.18 (d, J=1.0 Hz, 1H), 8.06 (dd,J=8.7, 1.6 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 5.24-5.33 (m, 1H), 5.16-5.24(m, 1H), 4.52-4.63 (m, 2H), 3.78-3.91 (m, 2H), 3.68 (d, J=1.0 Hz, 6H),2.65-2.79 (m, 2H), 2.46-2.61 (m, 2H), 2.05-2.26 (m, 4H), 1.07-1.20 (m,2H), 0.99-1.06 (m, 6H), 0.94-1.01 (m, 2H), 0.92 (dd, J=6.8, 3.3 Hz, 6H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

Methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

NCS (13.0 mg, 0.097 mmol) was added to a solution of methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(79 mg) in DMF (2 mL) at room temperature and the mixture was heated at50° C. for 16 h. The crude product was purified by prep HPLC (TFA) usinga Waters Sunfire C18 column 30×150 mm 5 u eluted with a gradient of 30to 90% MeOH-Water+0.1% TFA to yield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(20.2 mg) as yellow solid and a mixture of the two monochloride productswhich were separated by SFC on a CHIRALPAK® IB column and thenrepurified individually by prep HPLC (TFA) using a Waters Sunfire C18column 30×150 mm 5 u eluted with a gradient of 25 to 100% MeOH-Water+0.1TFA to yield a TFA of methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(11.1 mg) as a yellow solid and a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(11.4 mg) as a yellow solid.

For Example 60: LC-MS retention time 2.133 min; m/z 883.35 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.22 (s, 2H), 8.07 (d,J=8.5 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 7.83-7.95 (m, 6H), 5.08 (td,J=9.1, 6.0 Hz, 2H), 4.59 (dd, J=6.7, 1.8 Hz, 2H), 3.71-3.79 (m, 2H),3.68 (s, 6H), 2.44-2.57 (m, 4H), 2.13-2.25 (m, 2H), 2.00-2.10 (m, 2H),1.09-1.16 (m, 2H), 1.05 (dd, J=6.7, 1.5 Hz, 6H), 0.91-1.02 (m, 6H),0.79-0.87 (m, 2H).

For Example 62: LC-MS retention time 1.745 min; m/z 847.33 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.23 (s, 2H), 8.02-8.09(m, 2H), 7.98 (d, J=8.2 Hz, 2H), 7.89-7.94 (m, 3H), 7.86 (d, J=8.6 Hz,2H), 5.15 (dd, J=9.2, 7.0 Hz, 1H), 5.09 (t, J=7.0 Hz, 1H), 4.58 (t,J=6.7 Hz, 2H), 3.84 (t, J=4.7 Hz, 1H), 3.71-3.77 (m, 1H), 3.69 (d, J=3.1Hz, 6H), 2.72 (dd, J=13.7, 9.5 Hz, 1H), 2.45-2.54 (m, 3H), 2.14-2.24 (m,2H), 2.00-2.14 (m, 2H), 1.09-1.18 (m, 2H), 1.00-1.08 (m, 6H), 0.96 (t,J=7.6 Hz, 6H), 0.92 (br s, 1H), 0.83 (br s, 1H).

For Example 63: LC-MS retention time 1.753 min; m/z 847.32 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Sunfire 5 u C18 4.6×30 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where Solvent A was10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90% MeOH/0.1% TFA.MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.26 (d, J=7.0 Hz, 2H),8.13 (d, J=8.9 Hz, 1H), 8.04-8.10 (m, 1H), 7.95-8.01 (m, 2H), 7.89-7.95(m, 2H), 7.82-7.89 (m, 3H), 5.17 (dd, J=9.2, 7.0 Hz, 1H), 5.07 (t, J=7.2Hz, 1H), 4.58 (d, J=6.4 Hz, 2H), 3.81-3.88 (m, 1H), 3.71-3.76 (m, 1H),3.69 (d, J=4.6 Hz, 6H), 2.73 (dd, J=13.4, 9.5 Hz, 1H), 2.44-2.56 (m,3H), 2.14-2.25 (m, 2H), 2.08-2.14 (m, 1H), 1.09-1.18 (m, 2H,) 1.00-1.08(m, 6H), 0.96 (t, J=6.4 Hz, 6H), 0.92 (br s, 1H) 0.78-0.85 (m, 1H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

The reaction of Intermediate 105 and the appropriate boronic acid(prepared in a similar manner as Intermediate 66 using the appropriatestarting materials) via a coupling reaction similar to the preparationof Intermediate 106 yielded a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(91 mg) as a pale yellow solid. LC-MS retention time 1.362 min; m/z855.31 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Sunfire 5 u C18 4.6×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% TFA and Solvent B was 10% H₂O/90%MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LCin electrospray mode. ¹H NMR (500 MHz, MeOD) δ ppm 8.29 (s, 1H), 8.28(s, 1H), 8.14 (d, J=8.9 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 8.01-7.94 (m,4H), 7.93-7.91 (m, 1H), 7.90-7.83 (m, 3H), 5.19-5.12 (m, 2H), 4.62 (d,J=7.6 Hz, 1H), 4.58 (d, J=6.4 Hz, 1H), 3.99-3.91 (m, 2H), 3.89-3.80 (m,2H), 3.70 (s, 3H), 3.69 (s, 3H), 3.46-3.35 (m, 2H), 2.76-2.67 (m, 2H),2.57-2.46 (m, 2H), 2.25-2.16 (m, 1H), 2.15-2.05 (m, 3H), 1.65-1.40 (m,4H), 1.16-1.07 (m, 2H), 1.04 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.7 Hz, 3H),0.93-0.87 (m, 2H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

N-Chlorosuccinimide (10.4 mg, 0.078 mmol) was added to a stirredsolution of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(Example 61) (60 mg, 0.071 mmol) in DMF (1.5 mL) and the reaction vesselwas sealed and heated at 50° C. for 16 h. The reaction was cooled,partially concentrated and then diluted with MeOH. The solution wasfiltered and purified by preparative HPLC (MeOH/H₂O, w 0.1% TFA) toyield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(21.4 mg) as a yellow solid. LC-MS retention time 2.798 min; m/z 462.34(½ MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.18 (s, 2H), 8.03 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H),7.80-7.92 (m, 6H), 5.06 (ddd, J=9.0, 5.8, 3.5 Hz, 2H), 4.63 (d, J=7.5Hz, 1H), 4.57 (d, J=6.5 Hz, 1H), 3.92-3.98 (m, 2H), 3.71-3.81 (m, 2H),3.67 (s, 6H), 3.35-3.44 (m, 2H), 2.42-2.57 (m, 4H), 1.99-2.24 (m, 4H),1.40-1.66 (m, 4H), 1.06-1.14 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.95 (d,J=6.8 Hz, 3H), 0.82 (d, J=2.8 Hz, 2H).

Methyl((1S)-1-(4,4-difluorocyclohexyl)-2-((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-(4,4-difluorocyclohexyl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate

HATU (67.3 mg, 0.177 mmol) was added to a stirred solution of an HClsalt of(1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 69) (38.0 mg, 0.059 mmol) and(S)-2-(4,4-difluorocyclohexyl)-2-(methoxycarbonylamino)acetic acid (44.5mg, 0.177 mmol) in DMF (0.7 mL) and DIPEA (0.103 mL, 0.590 mmol). Thereaction was diluted with MeOH, filtered, purified by preparative HPLC(water/MeOH w/0.1% TFA) and repurified by preparative HPLC (water/MeOHw/10 mM ammonium acetate) to yield methyl((1S)-1-(4,4-difluorocyclohexyl)-2-((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-(4,4-difluorocyclohexyl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate(22.1 mg) as a light yellow solid. LC-MS retention time 2.713 min; m/z483.13 (½ MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.16 (s, 1H), 8.11 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.77-7.85 (m,5H), 7.47 (s, 1H), 7.39 (s, 1H), 7.08 (d, J=8.5 Hz, 1H), 5.15 (ddd,J=8.2, 6.3, 6.1 Hz, 2H), 4.68 (br. s., 2H), 3.69-3.76 (m, 2H), 3.68 (s,6H), 2.41-2.57 (m, 4H), 1.65-2.12 (m, 16H), 1.33-1.59 (m, 4H), 1.06-1.17(m, 2H), 0.78 (br. s., 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)butanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)propyl)carbamate

HATU (89 mg, 0.24 mmol) was added to a stirred solution of a TFA salt of(1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 69) (80 mg, 0.084 mmol) and(S)-2-(methoxycarbonylamino)butanoic acid (37.8 mg, 0.235 mmol) in DMF(0.8 mL) and DIPEA (0.15 mL, 0.84 mmol). The reaction was diluted withMeOH, filtered and purified by preparative HPLC (water/MeOH w/0.1% TFA)to yield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)butanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)propyl)carbamate(70.1 mg) as a light yellow solid. LC-MS retention time 1.688 min; m/z785.55 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.28 (s, 1H), 8.26 (s, 1H), 8.12 (d, J=8.8 Hz, 1H),8.07 (d, J=8.5 Hz, 1H), 7.93-8.00 (m, 4H), 7.82-7.90 (m, 4H), 5.12-5.21(m, 2H), 4.58-4.65 (m, 2H), 3.74-3.81 (m, 2H), 3.67 (s, 6H), 2.70 (ddd,J=13.7, 9.0, 4.9 Hz, 2H), 2.49 (dq, J=14.2, 7.1 Hz, 2H), 2.09 (br. s.,2H), 1.86-1.99 (m, 2H), 1.64-1.77 (m, 2H), 1.09-1.17 (m, 2H), 1.02 (t,J=7.4 Hz, 6H), 0.92 (br. s., 2H).

Methyl((1S)-1-(((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (101 mg, 0.266 mmol) was added to a stirred solution of a TFA saltof2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 117) (102 mg, 0.106 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (46.6 mg, 0.266 mmol)in DMF (1.0 mL) and DIPEA (0.189 mL, 1.1 mmol) and the reaction wasstirred at rt for 2 h. The reaction mixture was diluted with MeOH andpurified by preparative HPLC (MeOH/H₂O w/0.1% TFA) and then repurifiedby preparative HPLC (acetonitrile/water with 0.1% TFA) to yield a TFAsalt of methyl((1S)-1-(((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(63.8 mg) as a light yellow solid. LC-MS retention time 1.900 min; m/z817.59 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR presentsas a ˜4:1 mixture of regioisomers. ¹H NMR (for major regioisomer) (400MHz, MeOD) δ ppm 8.31 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.5 Hz, 1H),8.09 (d, J=8.5 Hz, 1H), 7.94-8.02 (m, 5H), 7.84-7.92 (m, 3H), 5.15-5.24(m, 2H), 4.13 (dd, J=8.7, 1.4 Hz, 2H), 3.74 (d, J=2.8 Hz, 2H), 3.67 (s,6H), 2.50-2.60 (m, 2H), 2.26-2.45 (m, 4H), 1.95-2.10 (m, 4H), 1.57 (dd,J=6.5, 3.0 Hz, 6H), 1.32 (t, J=6.4 Hz, 2H), 0.99 (d, J=6.8 Hz, 6H), 0.89(d, J=6.8 Hz, 6H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamateand

Methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

A mixture of two chloroimidazole regioisomers as TFA salts (Examples 68and 69) (21.4 mg) was isolated from the same reaction that prepared aTFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(Example 64). The two regioisomeric compounds were separated in multipleinjections using SCF chromatography (2-ethylpyridine SCF column (4.6×250mm, 5 μm) and 80% CO₂-20% EtOH/0.1% DEA). The absolute regiochemistry ofthe separated materials was determined by HMBC correlation. The reactionyielded methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(7.4 mg) and methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(4.5 mg), each as an off-white solid. For Example 68: LC-MS retentiontime 2.683 min; m/z 889.17 (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10 u C183.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 5% MeOH/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mM ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. For Example 69: LC-MS retention time 2.695 min; m/z889.22 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (73.3 mg, 0.193 mmol) was added to a stirred solution of a TFA saltof2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 117) (73.9 mg, 0.077 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(41.9 mg, 0.193 mmol) in DMF (1.0 mL) and DIPEA (0.14 mL, 0.77 mmol) andthe reaction was stirred at rt for 30 min. The reaction mixture wasdiluted with MeOH, filtered and purified by preparative HPLC (MeOH/H₂Ow/0.1% TFA) to yield a TFA salt of methyl((1S)-2-((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(51.2 mg) as a yellow solid. LC-MS retention time 1.897 min; m/z 901.39(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-1-(4,4-difluorocyclohexyl)-2-((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-((2S)-2-(4,4-difluorocyclohexyl)-2-((methoxycarbonyl)amino)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate

HATU (70.8 mg, 0.186 mmol) was added to a stirred solution of a TFA saltof2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 117) (71.4 mg, 0.074 mmol) and(S)-2-(4,4-difluorocyclohexyl)-2-(methoxycarbonylamino)acetic acid (46.8mg, 0.186 mmol) in DMF (1.0 mL) and DIPEA (0.13 mL, 0.75 mmol) and thereaction was stirred at rt for 1.5 h. The reaction was diluted withMeOH, filtered and purified in by preparative HPLC (MeOH/H₂O w/0.1% TFA)to yield the desired product a TFA salt of methyl((1S)-1-(4,4-difluorocyclohexyl)-2-((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-((2S)-2-(4,4-difluorocyclohexyl)-2-((methoxycarbonyl)amino)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate(43.3 mg) as a light yellow solid. LC-MS retention time 2.828 min; m/z485.22 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(4-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

N-Chlorosuccinimide (7.1 mg, 0.053 mmol) was added to a stirred solutionof methyl((1S)-2-((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(Example 34) (22.7 mg, 0.025 mmol) in DMF (0.5 mL) and the reactionvessel was sealed and the reaction was heated at 50° C. for 12 h. Thereaction was cooled to rt, additional N-chlorosuccinimide (˜3 mg) wasadded and the reaction vessel was sealed and stirred at 50° C. for 2 h.The reaction was cooled to rt, diluted with MeOH, filtered and purifiedby preparative HPLC (Methanol/Water w/0.1% TFA) to yield methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(4-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(12 mg) as a yellow solid. LC-MS retention time 2.708 min; m/z 483.25 (½MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.18 (s, 2H), 8.04 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H),7.80-7.92 (m, 6H), 5.02-5.09 (m, 2H), 4.63 (d, J=6.0 Hz, 2H), 3.91-3.99(m, 4H), 3.73-3.80 (m, 2H), 3.67 (s, 6H), 3.34-3.45 (m, 4H), 2.43-2.54(m, 4H), 1.98-2.13 (m, 4H), 1.38-1.67 (m, 8H), 1.06-1.15 (m, 2H), 0.81(br. s., 2H).

Methyl((1S,2R)-2-methoxy-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)propyl)carbamate

HATU (65.7 mg, 0.173 mmol) was added to a stirred solution of a TFA saltof2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 133) (66 mg, 0.069 mmol) and(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (33.0 mg, 0.173mmol) in DMF (0.8 mL) and DIPEA (0.121 mL, 0.691 mmol) and the reactionwas stirred at rt overnight. The reaction was diluted with MeOH,filtered and purified preparative HPLC (Methanol/water w/10 nM ammoniumacetate) to yield a TFA salt of methyl((1S,2R)-2-methoxy-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)propyl)carbamate(51.9 mg, 0.048 mmol, 98% yield) as an off-white solid. LC-MS retentiontime 2.383 min; m/z 845.42 (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10 u C183.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where Solvent A was 5% MeOH/95% H₂O/10 mMammonium acetate and Solvent B was 5% H₂O/95% MeOH/10 mM ammoniumacetate. MS data was determined using a MICROMASS® Platform for LC inelectrospray mode. ¹H NMR (MeOD, 400 MHz) δ 8.29 (br s, 1H), 8.26 (s,1H), 8.12 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 8.00-7.93 (m, 4H),7.91-7.82 (m, 4H), 5.18 (td, J=9.0, 7.0 Hz, 2H), 4.78 (dd, J=3.9, 1.7Hz, 2H), 3.92-3.79 (m, 4H), 3.68 (s, 6H), 3.35 (s, 3H), 3.35 (m, 3H),2.76-2.65 (m, 2H), 2.59-2.47 (m, 2H), 2.15-2.05 (m, 2H), 1.19 (d, J=6.3Hz, 6H), 1.16-1.07 (m, 2H), 0.94-0.84 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (193 mg, 0.506 mmol) was added to a stirred solution of an HCl saltof(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 124) (100 mg, 0.169 mmol) and(R)-2-(methoxycarbonylamino)-3-methylbutanoic acid (89 mg, 0.51 mmol) inDMF (1.5 mL) and DIPEA (0.24 mL, 1.4 mmol) and the clear orange solutionwas stirred at rt for 3 h. The reaction was diluted with methanol,filtered and purified by preparative HPLC (MeOH/water with an ammoniumacetate buffer) to yield methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(71 mg) as a light yellow solid. LC-MS retention time 3.706 min; m/z761.22 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz, MeOD)δ ppm 8.15 (s, 1H), 7.96 (s, 1H), 7.80-7.88 (m, 3H), 7.51 (dd, J=8.4,1.6 Hz, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 5.18 (dd, J=9.0, 4.8 Hz, 1H),5.13 (dd, J=8.8, 4.3 Hz, 1H), 4.59 (dd, J=11.8, 6.8 Hz, 2H), 3.68-3.72(m, 1H), 3.67 (s, 3H), 3.67 (s, 3H), 3.59-3.64 (m, 1H), 2.31-2.60 (m,4H), 2.08-2.22 (m, 2H), 1.99-2.08 (m, 2H), 1.13 (ddd, J=8.6, 5.8, 5.5Hz, 2H), 1.00 (dd, J=12.9, 6.9 Hz, 6H), 0.93 (dd, J=6.7, 2.9 Hz, 6H),0.79 (br. s., 2H).

Mixture of Diastereomers Methyl(2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(((methoxycarbonyl)amino)(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (110 mg, 0.289 mmol) was added to a stirred solution of an HCl saltof(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 124) (57 mg, 0.096 mmol) and racemic2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (62.7mg, 0.289 mmol) in DMF (1.0 mL) and DIPEA (0.134 mL, 0.770 mmol) and theclear orange solution was stirred at rt for 3 h. The reaction wasdiluted with methanol, filtered and purified by preparative HPLC(MeOH/water with an ammonium acetate buffer) to yield methyl(2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(((methoxycarbonyl)amino)(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(37.3 mg) as a yellow solid and as a mixture of diastereomers. LC-MSretention time 1.522 min; m/z 845.36 (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 1mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where Solvent A was 10% MeOH/90% H₂O/0.1%trifluoroacetic acid and Solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. Mixture of diastereomers. ¹H NMR (400 MHz,MeOD) δ ppm 8.15 (d, J=12.8 Hz, 1H), 7.96 (s, 1H), 7.80-7.90 (m, 3H),7.51 (dd, J=8.5, 1.5 Hz, 1H), 7.46 (d, J=5.5 Hz, 1H), 7.27 (d, J=5.3 Hz,1H), 5.08-5.24 (m, 2H), 4.61-4.69 (m, 1H), 4.57 (dd, J=8.3, 4.5 Hz, 1H),3.85-4.03 (m, 5H), 3.63-3.79 (m, 8H), 3.34-3.49 (m, 5H), 2.30-2.63 (m,4H), 1.99-2.16 (m, 3H), 1.70-1.80 (m, 1H), 1.35-1.66 (m, 6H), 1.16-1.26(m, 1H), 1.07-1.16 (m, 1H), 0.70-0.83 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-((4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

N-Chlorosuccinimide (13.3 mg, 0.100 mmol) was added to a stirredsolution of((1S)-1-(((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(38 mg, 0.050 mmol) in DMF (1 mL) and then the reaction vessel wasflushed with nitrogen, sealed and heated at 50° C. for 16 h. Thereaction was cooled to rt and additional N-chlorosuccinimide (7.4 mg)was added. The reaction was reheated at 50° C. for 3 h, cooled to rt,diluted with MeOH (˜0.5 mL), filtered and purified by preparative HPLC(MeOH/water, TFA buffer) to yield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-((4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(5.0 mg) as a yellow solid. LC-MS retention time 4.153 min; m/z 831.02(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.19 (s, 1H), 8.07 (s, 1H), 7.87-7.99 (m, 3H), 7.58(dd, J=8.5, 1.3 Hz, 1H), 5.07 (t, J=7.2 Hz, 1H), 4.98-5.03 (m, 1H),4.54-4.59 (m, 2H), 3.67 (s, 6H), 3.62-3.75 (m, 2H), 2.45-2.50 (m, 2H),2.41 (dd, J=7.3, 3.5 Hz, 2H), 2.09-2.21 (m, 2H), 1.96-2.08 (m, 2H),1.08-1.16 (m, 2H), 1.02 (t, J=6.1 Hz, 6H), 0.92-0.97 (m, 6H), 0.75-0.85(m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (25.4 mg, 0.067 mmol) was added to a stirred solution of an HClsalt of methyl(S)-1-((1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(Intermediate 128) (42 mg, 0.061 mmol),2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)aceticacid (Cap-179 stereoisomer 2) (14.9 mg, 0.061 mmol) and DIEA (0.053 mL,0.30 mmol) in DMF (2 mL) and the resulting yellowish solution wasstirred at rt for 2 h. The reaction was concentrated under reducedpressure and the residue was redissolved into methanol and purified bypreparative HPLC. (Solvent A: 05% MeCN/95% water/10 mM NH₄Ac; Solvent B:95% MeCN/5% water/10 mM NH₄Ac; Column: Sunfire Prep MS C18 30×100 mmS10; Wavelength: 220 nM; Flow rate: 40 ml/min; Gradient: 0% B to 80% Bover 30 min with a 5 min. hold time) to yield methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(26 mg) as a white solid. LC-MS [M+H]⁺=883; Rt=2.99 min is product.Column Luna 3 u C18 2×50 mm; start % B: 0, final % B: 100 Solvent A: 5%ACN/95% H₂O+10 mM Ammonium Acetate; Solvent B: 95% ACN/5% H₂O+10 mMAmmonium Acetate; flow rate 4 ml/min. Run time: 5 min. Purity=97%. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 11.85 (1H, br. s.), 11.73 (1H, br. s.),8.14-8.27 (2H, m), 7.90-7.98 (3H, m), 7.82-7.89 (3H, m), 7.79 (2H, d,J=8.24 Hz), 7.64 (1H, s), 7.57 (1H, s), 7.19 (2H, t, J=9.31 Hz),5.03-5.13 (2H, m), 4.51 (1H, t, J=7.93 Hz), 4.44 (1H, t, J=7.78 Hz),3.65 (1H, br. s.), 3.51-3.60 (7H, m), 3.29-3.42 (7H, m), 2.35-2.47 (2H,m), 2.20-2.33 (2H, m), 2.01-2.11 (2H, m), 1.83-1.92 (3H, m), 1.63 (1H,d, J=12.21 Hz), 1.57 (1H, d, J=11.60 Hz), 0.96-1.09 (12H, m), 0.89 (4H,d, J=6.71 Hz), 0.72 (2H, br. s.).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6′-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2,2′-binaphthalen-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (91 mg, 0.240 mmol) was added to a stirred solution of6,6′-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)-2,2′-binaphthyl(Intermediate 133) (43.9 mg, 0.080 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (42.0 mg, 0.240 mmol)in DMF (1 mL) and DIPEA (0.14 mL, 0.80 mmol) and the clear brownsolution was stirred for 2 h. The reaction mixture was diluted with MeOHand purified by preparative HPLC (MeOH/water with 0.1% TFA) purified byto yield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6′-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2,2′-binaphthalen-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(28.9 mg) as a yellow solid. LC-MS retention time 1.788 min; m/z 863.46(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.37 (s, 2H), 8.29 (d, J=1.0 Hz, 2H), 8.15 (d, J=8.8Hz, 2H), 8.06-8.13 (m, 4H), 7.97 (s, 2H), 7.86 (dd, J=8.7, 1.6 Hz, 2H),5.17 (dd, J=9.3, 7.0 Hz, 2H), 4.57 (d, J=6.8 Hz, 2H), 3.80-3.86 (m, 2H),3.68 (s, 6H), 2.71 (dd, J=13.7, 9.4 Hz, 2H), 2.46-2.56 (m, 2H),2.15-2.25 (m, 2H), 2.09 (d, J=8.0 Hz, 2H), 1.08-1.16 (m, 2H), 1.03 (d,J=6.8 Hz, 6H), 0.92-0.96 (m, 6H), 0.88-0.96 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,5R)-2-((2S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (35.4 mg, 0.093 mmol) was added to a stirred solution of a TFA saltof methyl(2S)-1-((1R,3S,5R)-3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(47 mg, 0.072 mmol) and(S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)aceticacid (23 mg, 0.093 mmol) in DMF (1 mL) and DIPEA (0.050 mL, 0.29 mmol)and the reaction was stirred for 3 h. The reaction mixture was dilutedwith MeOH and purified by preparative HPLC (MeOH/water with 0.1% TFA) toyield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,5R)-2-((2S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(31.3 mg) as a yellow solid. LC-MS retention time 1.670 min; m/z 883.43(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.28 (d, J=1.0 Hz, 1H), 8.26 (s, 1H), 8.12 (d, J=8.8Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.93-7.99 (m, 4H), 7.82-7.92 (m, 4H),5.15 (td, J=9.6, 6.9 Hz, 2H), 4.58 (t, J=7.4 Hz, 2H), 3.79-3.86 (m, 2H),3.68 (s, 6H), 3.43-3.53 (m, 2H), 2.65-2.75 (m, 2H), 2.50 (ddd, J=13.6,6.7, 6.5 Hz, 2H), 2.04-2.24 (m, 4H), 1.54-1.62 (m, 1H), 1.45-1.53 (m,1H), 0.84-1.21 (m, 18H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (64.1 mg, 0.169 mmol) was added to a solution of an HCl salt of2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)quinoline(Intermediate 139) (50 mg, 0.073 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (29.5 mg, 0.169 mmol)in DMF (1 mL) and DIPEA (0.115 mL, 0.660 mmol) and the reaction mixturewas stirred at rt for 16 h. The reaction was diluted with MeOH, filteredand purified by preparative HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(55.3 mg) as a yellow solid. LC-MS retention time 2.883 min; m/z 814.65(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (64.1 mg, 0.169 mmol) was added to a solution of an HCl salt of2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)quinoline(Intermediate 139) (50 mg, 0.073 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(36.6 mg, 0.169 mmol) in DMF (1 mL) and DIPEA (0.12 mL, 0.66 mmol) andthe reaction mixture was stirred at rt for 2 h. The reaction was dilutedwith MeOH, filtered and purified by preparative HPLC (H₂O-MeOH with 0.1%TFA buffer) to yield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(64.8 mg) as a yellow solid. LC-MS retention time 2.553 min; m/z 898.70(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (102 mg, 0.269 mmol) was added to a stirred solution of an HCl saltof(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(60 mg, 0.134 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(58.4 mg, 0.269 mmol) in DMF (1.2 mL) and DIPEA (0.19 mL, 1.1 mmol) andthe reaction was stirred at rt for 2 h. The reaction was diluted withmethanol and purified by preparative HPLC (MeOH/water, with an ammoniumacetate buffer) to yield methyl((1S)-2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(48.9 mg) as a light yellow solid. LC-MS retention time 2.572 min; m/z845.65 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.14 (s, 1H), 7.96 (s, 1H), 7.80-7.87 (m, 3H), 7.51(dd, J=8.5, 1.5 Hz, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 5.16 (dd, J=8.8,5.0 Hz, 1H), 5.11 (dd, J=8.8, 4.5 Hz, 1H), 4.66 (d, J=7.5 Hz, 1H), 4.63(d, J=7.8 Hz, 1H), 3.90-3.98 (m, 4H), 3.67 (s, 6H), 3.63-3.76 (m, 2H),3.33-3.44 (m, 4H), 2.32-2.56 (m, 4H), 1.98-2.10 (m, 4H), 1.35-1.67 (m,8H), 1.08-1.16 (m, 2H), 0.78 (br. s., 2H).

Methyl((1S)-2-((1R,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (27.8 mg, 0.073 mmol) was added to a solution of methyl(2S)-1-((1R,3S,5R)-3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(Intermediate 131) (40 mg, 0.061 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(15.90 mg, 0.073 mmol) were dissolved into DMF (0.5 mL) and DIPEA (0.053mL, 0.31 mmol) and the reaction was stirred at rt for 2 h. The reactionwas diluted with methanol and purified by preparative HPLC (MeOH/waterwith an ammonium acetate buffer) to yield methyl((1S)-2-((1R,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(3.5 mg) as a light yellow solid. LC-MS retention time 2.785 min; m/z855.74 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.17 (s, 1H), 8.10 (s, 1H), 7.93 (dd, J=8.5, 3.0 Hz,2H), 7.77-7.86 (m, 6H), 7.44 (s, 1H), 7.35 (s, 1H), 5.20 (dd, J=8.9, 4.6Hz, 1H), 5.15 (dd, J=8.8, 5.0 Hz, 1H), 4.66 (d, J=7.8 Hz, 1H), 4.61 (d,J=6.8 Hz, 1H), 3.90-3.99 (m, 2H), 3.68 (s, 6H), 3.64-3.76 (m, 3H),3.34-3.43 (m, 3H), 2.39-2.61 (m, 4H), 2.12-2.23 (m, 1H), 1.99-2.10 (m,2H), 1.52-1.67 (m, 2H), 1.41-1.51 (m, 1H), 1.08-1.18 (m, 2H), 1.02 (d,J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H), 0.76-0.84 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamateand

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

N-Chlorosuccinimide (6.01 mg, 0.045 mmol) was added to a stirredsolution of a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(Example 80) (26 mg, 0.022 mmol) in DMF (0.5 mL) and the reactionmixture was stirred at 50° C. for 16 h. The reaction was diluted withMeOH, filtered and purified by preparative HPLC (H₂O-MeOH with 0.1% TFAbuffer) to yield two products: 1) A TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(12.4 mg) as yellow solid. LC-MS retention time 3.871 min; m/z 882.55(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.53 (d, J=8.8 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.23(s, 1H), 8.17 (s, 2H), 7.82-7.93 (m, 4H), 5.16 (dd, J=8.8, 5.3 Hz, 1H),5.06 (t, J=7.2 Hz, 1H), 4.53-4.63 (m, 2H), 3.68-3.76 (m, 2H), 3.67 (s,6H), 2.44-2.60 (m, 4H), 2.11-2.24 (m, 2H), 1.97-2.09 (m, 2H), 1.09-1.18(m, 2H), 1.03 (dd, J=6.8, 3.3 Hz, 6H), 0.95 (dd, J=6.8, 2.4 Hz, 6H),0.75-0.87 (m, 2H). 2) A TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(4.8 mg) as yellow solid. LC-MS retention time 2.98 min; m/z 848.60(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.64 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.32 (s, 1H),8.25-8.29 (m, 2H), 8.09 (d, J=8.8 Hz, 1H), 7.86-7.96 (m, 4H), 5.18-5.25(m, 1H), 5.03-5.09 (m, 1H), 4.53-4.62 (m, 2H), 3.64-3.83 (m, 2H),3.64-3.69 (m, 6H), 2.42-2.70 (m, 4H), 1.97-2.24 (m, 4H), 1.08-1.17 (m,2H), 1.02 (dd, J=6.8, 2.4 Hz, 6H), 0.94 (t, J=6.8 Hz, 6H), 0.76-0.91 (m,2H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

N-Chlorosuccinimide (6.68 mg, 0.050 mmol) was added to a solution of aTFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(Example 81) (31 mg, 0.025 mmol) in DMF (0.5 mL) and the reactionmixture was stirred at 50° C. for 16 h. The reaction was diluted withMeOH, filtered and purified by preparative HPLC (H₂O-MeOH with 0.1% TFAbuffer) to yield methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(12.1 mg) as yellow solid. LC-MS retention time 3.511 min; m/z 484.17 (½MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.60 (d, J=8.8 Hz, 1H), 8.27-8.33 (m, 2H), 8.21 (s,2H), 7.89-7.95 (m, 2H), 7.83-7.88 (m, 2H), 5.15 (dd, J=8.7, 5.6 Hz, 1H),5.05 (dd, J=8.3, 6.3 Hz, 1H), 4.64 (dd, J=11.3, 7.8 Hz, 2H), 3.87-4.00(m, 4H), 3.73-3.81 (m, 2H), 3.68 (s, 6H), 3.33-3.48 (m, 4H), 2.41-2.61(m, 4H), 1.95-2.16 (m, 4H), 1.39-1.70 (m, 8H), 1.06-1.18 (m, 2H), 0.81(m, 2H).

Methyl((1S)-1-(((2S,5S)-2-(4-chloro-5-(4-(6-(4-chloro-2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

N-Chlorosuccinimide (18.88 mg, 0.141 mmol) was to a stirred solution ofa TFA salt of methyl((1S)-1-(((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(105 mg, 0.129 mmol) in DMF (3.0 mL) and then and the reaction wasflushed with nitrogen, sealed and heated at 50° C. overnight. By LC-MS a1.3:1.6:1 of starting material: mono-C1 (presumably both regioisomers:dichloro). The reaction was concentrated, dissolved into MeOH, filteredand purified by preparative HPLC (MeOH/water with a TFA buffer) to yieldrecovered starting material (36.2 mg), a mixture of the twomono-chloroimidazole regioisomers (56.6 mg) (Example 94 and Example 95)and a TFA salt of methyl((1S)-1-(((2S,5S)-2-(4-chloro-5-(4-(6-(4-chloro-2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(20.4 mg) as a yellow solid. LC-MS retention time 2.482 min; m/z 885.84(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(5-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-1-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (62.8 mg, 0.165 mmol) was added to a stirred solution of an HClsalt of(1R,3S,5R)-3-(5-(4-(5-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 144) (42.6 mg, 0.066 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (28.9 mg, 0.165 mmol)in DMF (0.8 mL) and DIPEA (0.092 mL, 0.53 mmol) and the reaction wasstirred at rt for 2 h. The reaction was diluted with MeOH, filtered andpurified by preparative HPLC (MeOH/water with TFA buffer) to yield the aTFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(5-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-1-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(53.7 mg) as an off-white solid. LC-MS retention time 2.821 min; m/z813.88 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (500MHz, MeOD) δ ppm 8.06 (d, J=8.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.95(s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.78 (s, 1H), 7.65-7.73 (m, 4H),7.59-7.64 (m, 2H), 5.18 (ddd, J=12.5, 9.2, 7.0 Hz, 2H), 4.59 (dd, J=6.4,3.4 Hz, 2H), 3.80-3.87 (m, 2H), 3.69 (s, 6H), 2.73 (dt, J=13.4, 9.2 Hz,2H), 2.48-2.59 (m, 2H), 2.18-2.28 (m, 2H), 2.10 (br. s., 2H), 1.08-1.15(m, 2H), 1.06 (d, J=7.0 Hz, 3H), 1.04 (d, J=7.0 Hz, 3H), 0.99 (d, J=6.7Hz, 3H), 0.95 (d, J=6.7 Hz, 3H), 0.89-0.94 (m, 2H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(4-(5-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-1-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (62.8 mg, 0.165 mmol) was added to a stirred solution of an HClsalt of(1R,3S,5R)-3-(5-(4-(5-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 144) (42.6 mg, 0.066 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(35.9 mg, 0.165 mmol) in DMF (0.8 mL) and DIPEA (0.092 mL, 0.53 mmol)and the reaction was stirred at rt for 4 h. The reaction was dilutedwith MeOH, filtered and purified by preparative HPLC (MeOH/water withammonium acetate buffer) to yield methyl((1S)-2-((1R,3S,5R)-3-(4-(4-(5-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-1-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(42.6 mg, 0.066 mmol) as an off-white solid. LC-MS retention time 1.965min; m/z 897.59 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 1 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (500 MHz, MeOD)δ ppm 8.23 (d, J=8.2 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.2 Hz,2H), 7.52-7.59 (m, 2H), 7.44-7.51 (m, 4H), 7.41 (s, 1H), 7.21 (s, 1H),5.23 (dd, J=8.9, 4.6 Hz, 1H), 5.18 (dd, J=8.9, 4.9 Hz, 1H), 4.68 (dd,J=7.5, 2.6 Hz, 2H), 3.89-4.01 (m, 4H), 3.70-3.77 (m, 2H), 3.69 (s, 6H),3.35-3.45 (m, 4H), 2.43-2.63 (m, 4H), 2.00-2.14 (m, 4H), 1.52-1.71 (m,6H), 1.41-1.52 (m, 2H), 1.10-1.18 (m, 2H), 0.79-0.86 (m, 2H).

Methyl((1S)-1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((1R,3S,5R)-3-(4-((6-(2-((1R,3S,5R)-2-((2S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate

An HCl salt of(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 124) (50 mg, 0.073 mmol),2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)aceticacid (Cap-179 stereoisomer 2) (36.9 mg, 0.151 mmol), HATU (58.6 mg,0.154 mmol) and DIEA (0.077 mL, 0.441 mmol) were combined in DMF (3 mL)and the resulting yellow solution was stirred at rt for 15 h. Thevolatiles were removed under reduced pressure and the residue wasredissolved in methanol and purified by preparative HPLC (Solvent A: 10%MeOH/90% water/0.1% TFA; Solvent B: 90% MeOH/10% water/0.1% TFA; Column:Sunfire Prep MS C18 30×100 mm 5 u; Wavelength: 220 nM; Flow rate: 40ml/min; Gradient: 10% B to 80% B over 30 min. with a 5 min hold time) toyield a TFA salt of methyl((1S)-1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((1R,3S,5R)-3-(4-((6-(2-((1R,3S,5R)-2-((2S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate(43 mg) as a white solid. LC-MS [M+H]⁺=902; Rt=1.93 min is product.Column PHENOMENEX® 10 u C18 3.0×50 mm; start % B: 0, final % B: 100Solvent A: 10% MeOH/90% H₂O+1% TFA; Solvent B: 90% MeOH/10% H₂O+1% TFA;flow rate 4 mL/min. Run time: 5 min. Purity=98%. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.38 (1H, br. s.), 8.14-8.22 (1H, m), 8.09 (1H, d, J=8.85Hz), 7.93-8.00 (2H, m), 7.62 (1H, d, J=8.85 Hz), 7.25 (2H, t, J=7.48Hz), 5.02 (2H, t, J=6.87 Hz), 4.51 (1H, dd, J=7.78, 6.56 Hz), 4.45 (1H,t, J=7.93 Hz), 3.82 (1H, br. s.), 3.67 (1H, d, J=13.73 Hz), 3.54 (6H,s), 3.31-3.42 (3H, m), 2.33 (2H, br. s.), 1.85-1.97 (2H, m), 1.43-1.52(1H, m), 1.22-1.31 (1H, m), 1.03-1.12 (10H, m), 0.89-1.01 (9H, m), 0.82(1H, br. s.), 0.75 (1H, br. s.).

Methyl((1S)-1-(((2S,3aS,6aS)-2-(4-(6-(4-(2-((2S,3aS,6aS)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)carbonyl)-2-methylpropyl)carbamate

HATU (60.9 mg, 0.160 mmol) was added to a stirred solution of an HClsalt of(2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)octahydrocyclopenta[b]pyrrole(51 mg, 0.073 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(Intermediate 147) (28.1 mg, 0.160 mmol) and DIPEA (0.076 mL, 0.44 mmol)in DCM (1.5 mL) and the reaction mixture was stirred at rt for 2 h. Thecrude reaction mixture was concentrated to dryness and purified bypreparative HPLC (TFA buffer) to yield a TFA salt of methyl((1S)-1-(((2S,3aS,6aS)-2-(4-(6-(4-(2-((2S,3aS,6aS)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)carbonyl)-2-methylpropyl)carbamate(23.7 mg) as a white solid. LC-MS retention time 2.462 min; m/z 867.8(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and SolventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-((2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)hexahydrocyclopenta[b]pyrrol-2(2H)-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (62.1 mg, 0.163 mmol) was added to a stirred solution of an HClsalt of(2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)octahydrocyclopenta[b]pyrrole(51 mg, 0.073 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(Intermediate 147) (52 mg, 0.074 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(35.5 mg, 0.163 mmol) and DIPEA (0.078 mL, 0.45 mmol) in DCM (1.5 mL)and the mixture was stirred at rt for 2 h. The crude reaction mixturewas concentrated to dryness and purified by preparative HPLC 9TFAbuffer) to yield a TFA salt of methyl((1S)-2-((2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)hexahydrocyclopenta[b]pyrrol-2(2H)-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(25.8 mg) as a white solid. LC-MS retention time 2.350 min; m/z 477.5 (½MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and SolventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

3-Chloro-1-(((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-5-methoxyisoquinoline

HATU (48.1 mg, 0.127 mmol) was added to a solution of an HCl salt of(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 124) (30 mg, 0.051 mmol) and3-chloro-5-methoxyisoquinoline-1-carboxylic acid (30.1 mg, 0.127 mmol)in DMF (0.8 mL) and DIPEA (0.071 mL, 0.45 mmol) and stirred at rtovernight. The reaction was diluted with MeOH, filtered, and purified bypreparative HPLC (MeOH/water with an NH₄OAc buffer) and repurified bypreparative HPLC (MeOH/water with a TFA buffer) to yield a TFA salt of3-chloro-1-(((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-5-methoxyisoquinoline(40.9 mg) as a yellow solid. LC-MS retention time 3.621 min; m/z 887.34(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-1-(((2S,5S)-2-(4-(4-(6-(4-chloro-2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamateand

Methyl((1S)-1-(((2S,5S)-2-(4-chloro-5-(4-(6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

These two compounds were prepared in the reaction that prepared methyl((1S)-1-(((2S,5S)-2-(4-chloro-5-(4-(6-(4-chloro-2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(Example 87) and they were isolated as a mixture of mono-chloroimidazoleregioisomers. The two regioisomers were separated by SCFC on aCHIRALCEL® OJ-H column (30×250 mm, 5 μm) using Solvents: 75% CO₂-25%EtOH/0.1% DEA. The absolute regiochemistry of the twomono-chloroimidazole regioisomers was not determined so each wasarbitrarily assigned. Example 94: Methyl((1S)-1-(((2S,5S)-2-(4-(4-(6-(4-chloro-2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(18.6 mg) was isolated as a yellow solid. LC-MS retention time 3.756min; m/z 851.62 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. Example 95:Methyl((1S)-1-(((2S,5S)-2-(4-chloro-5-(4-(6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(24.1 mg) was isolated as a yellow solid. LC-MS retention time 3.770min; m/z 851.64 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-((1R,3S,5R)-3-(4-((6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

4M HCl (0.370 mL, 1.48 mmol) in dioxane was added to a solution of(1R,3S,5R)-tert-butyl3-(5-((6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 150) (69 mg, 0.074 mmol) in dioxane (2 mL) and slurry wasstirred for 1.5 h. The reaction mixture was then concentrated under astream of nitrogen and the intermediate product was treated with(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(20.9 mg, 0.096 mmol), DMF (1.5 mL), DIPEA (0.078 mL, 0.44 mmol) andfinally HATU (36.6 mg, 0.096 mmol). The reaction mixture was stirred atrt overnight, diluted with MeOH, filtered and purified by preparativeHPLC (MeOH/water with 0.1% TFA) to yield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-((6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(35.3 mg) as a yellow solid. LC-MS retention time 2.726 min; m/z 803.74(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.27 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=8.8 Hz, 1H),7.98-8.02 (m, 2H), 7.88 (dd, J=8.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.67 (dd,J=8.5, 1.5 Hz, 1H), 5.15 (dd, J=9.3, 7.0 Hz, 1H), 5.09 (dd, J=9.0, 6.3Hz, 1H), 4.59 (d, J=7.8 Hz, 1H), 4.56 (d, J=6.5 Hz, 1H), 3.91-4.00 (m,2H), 3.74-3.84 (m, 2H), 3.67 (s, 6H), 3.34-3.45 (m, 2H), 2.70 (dd,J=13.6, 9.5 Hz, 1H), 2.61 (dd, J=13.8, 8.8 Hz, 1H), 2.40-2.54 (m, 2H),2.14-2.23 (m, 1H), 2.01-2.13 (m, 3H), 1.56-1.64 (m, 1H), 1.38-1.55 (m,3H), 1.05-1.14 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H),0.82-0.92 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

4M HCl (0.34 mL, 1.3 mmol) in dioxane was added to a solution of(1R,3S,5R)-tert-butyl3-(5-((6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 150) (62.7 mg, 0.067 mmol) in dioxane (2 mL) the slurrywas stirred for 1.5 h. The reaction was then concentrated under a streamof nitrogen to dryness and then treated with2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)aceticacid (Cap-179 stereoisomer 2) (21.45 mg, 0.087 mmol), DMF (1.5 mL),DIPEA (0.071 mL, 0.40 mmol) and finally HATU (33.3 mg, 0.087 mmol). Thereaction mixture was stirred at rt overnight diluted with MeOH, filteredand purified by preparative HPLC (MeOH/water with 0.1% TFA) to yield aTFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(28 mg) as a yellow solid. LC-MS retention time 2.898 min; m/z 831.80(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.27 (s, 1H), 8.17 (s, 1H), 8.05 (d, J=8.8 Hz, 1H),7.98-8.02 (m, 2H), 7.88 (dd, J=8.5, 1.8 Hz, 1H), 7.74 (s, 1H), 7.66 (dd,J=8.5, 1.5 Hz, 1H), 5.15 (dd, J=9.2, 6.9 Hz, 1H), 5.10 (dd, J=9.0, 6.3Hz, 1H), 4.56 (t, J=6.0 Hz, 2H), 3.73-3.85 (m, 2H), 3.67 (s, 6H),3.43-3.54 (m, 2H), 2.70 (dd, J=13.7, 9.4 Hz, 1H), 2.61 (dd, J=13.6, 9.0Hz, 1H), 2.40-2.54 (m, 2H), 2.01-2.23 (m, 4H), 1.55-1.64 (m, 1H), 1.46(d, J=12.0 Hz, 1H), 1.17 (dd, J=6.0, 4.3 Hz, 6H), 1.04-1.13 (m, 3H),1.01 (d, J=6.8 Hz, 3H), 0.96-1.03 (m, 1H), 0.92 (d, J=6.8 Hz, 3H),0.88-0.93 (m, 1H), 0.82-0.87 (m, 1H).

Methyl((1S)-2-((2S,5S)-2-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (43.2 mg, 0.114 mmol) was added an HCl salt of(1R,3S,5R)-3-(4-((6-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 154) (27 mg, 0.045 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(24.7 mg, 0.114 mmol) in DMF (1 mL) and DIPEA (0.056 mL, 0.32 mmol) andthe reaction mixture was stirred at rt for 2 h. The reaction wasconcentrated under a stream of nitrogen, dissolved into MeOH, filteredand purified by preparative HPLC (MeOH/water with 0.1% TFA buffer) toyield a TFA salt of methyl((1S)-2-((2S,5S)-2-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(31.4 mg) as a yellow solid. LC-MS retention time 2.658 min; m/z 847.80(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. The ¹H NMRpresents as a ˜1:3.5 mixture of rotamers. The ¹H NMR for the majorrotamer is: ¹H NMR (400 MHz, MeOD) δ ppm 8.29 (s, 1H), 8.18 (s, 1H),8.06 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.89 (dd,J=8.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.67 (dd, J=8.4, 1.4 Hz, 1H), 5.19(dd, J=10.5, 7.0 Hz, 1H), 5.09 (dd, J=8.9, 6.4 Hz, 1H), 4.59 (d, J=7.5Hz, 1H), 4.22 (d, J=9.3 Hz, 1H), 3.86-4.00 (m, 4H), 3.72-3.82 (m, 2H),3.67 (s, 6H), 3.23-3.45 (m, 4H), 2.50-2.70 (m, 2H), 2.24-2.50 (m, 3H),1.90-2.13 (m, 4H), 1.70-1.85 (m, 1H), 1.57 (d, J=6.5 Hz, 3H), 1.30-1.64(m, 6H), 1.23 (d, J=11.5 Hz, 1H), 1.04-1.12 (m, 1H), 0.85 (br. s., 1H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-((6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (43.2 mg, 0.114 mmol) was added to a stirred solution of an HClsalt of(1R,3S,5R)-3-(4-((6-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 154) (10.1 mg, 0.017 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (7.44 mg, 0.042 mmol)in DMF (0.5 mL) and DIPEA (0.021 mL, 0.119 mmol) and the reactionmixture was stirred at rt for 2 h. The reaction was concentrated,dissolved into MeOH, filtered and purified by preparative HPLC(MeOH/water with 0.1% TFA buffer) to yield a TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-((6-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(9.3 mg) as a yellow solid. LC-MS retention time 2.930 min; m/z 763.75(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR presentsas a ˜1:3 mixture of rotamers, the data for the major rotamer is: ¹H NMR(400 MHz, MeOD) δ ppm 8.30 (s, 1H), 8.19 (s, 1H), 8.07 (d, J=8.8 Hz,1H), 7.99-8.03 (m, 2H), 7.90 (dd, J=8.5, 1.5 Hz, 1H), 7.77 (s, 1H),7.65-7.71 (m, 1H), 5.19 (dd, J=10.2, 6.9 Hz, 1H), 5.10 (dd, J=9.2, 6.4Hz, 1H), 4.55 (d, J=6.5 Hz, 1H), 4.13 (d, J=8.8 Hz, 1H), 3.67 (s, 6H),3.65-3.79 (m, 2H), 1.95-2.68 (m, 8H), 1.57 (d, J=6.5 Hz, 3H), 1.31 (d,J=6.3 Hz, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H), 0.93 (d,J=6.8 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H), 0.84-1.14 (m, 2H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

4M HCl (0.32 mL, 1.3 mmol) in dioxane was added to mixture of a TFA saltof (1R,3S,5R)-tert-butyl3-(5-(6-((2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 158) (60 mg, 0.064 mmol) in dioxane (0.5 mL) and thereaction was stirred vigorously for 4 h. The reaction was concentratedto dryness. Then(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(18.2 mg, 0.084 mmol), DMF (0.5 mL), DIPEA (0.067 mL, 0.39 mmol) andfinally HATU (31.8 mg) were added to the crude material and the reactionwas stirred at rt for 1 h. The reaction was partially concentrated witha stream on nitrogen, diluted with MeOH, filtered and purifiedpreparative HPLC (MeOH/water with a TFA buffer) and then repurifiedpreparative HPLC (MeOH/water with an ammonium acetate buffer). Thematerial was purified a third time by preparative HPLC (MeOH/water witha TFA buffer) to yield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(27.7 mg) as a white solid. LC-MS retention time 3.291 min; m/z 803.67(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.27 (s, 1H), 8.19 (s, 1H), 8.06 (d, J=8.8 Hz, 1H),7.99-8.03 (m, 2H), 7.88 (dd, J=8.5, 1.8 Hz, 1H), 7.78 (s, 1H), 7.68 (dd,J=8.5, 1.5 Hz, 1H), 5.15 (dd, J=9.0, 7.0 Hz, 1H), 5.09 (dd, J=9.3, 6.5Hz, 1H), 4.80 (d, 2H), 4.54 (d, J=6.5 Hz, 1H), 3.87-3.93 (m, 1H),3.70-3.79 (m, 3H), 3.68 (s, 3H), 3.67 (s, 3H), 3.54-3.63 (m, 1H),3.34-3.40 (m, 1H), 2.59-2.74 (m, 2H), 2.40-2.55 (m, 2H), 2.00-2.22 (m,4H), 1.71-1.81 (m, 2H), 1.51-1.63 (m, 2H), 1.05-1.14 (m, 2H), 1.01 (d,J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 0.88 (br. s., 2H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-((3S)-tetrahydro-2H-pyran-3-yl)ethyl)carbamate

4M HCl (0.3 mL, 1.3 mmol) in dioxane was added to mixture of a TFA saltof (1R,3S,5R)-tert-butyl3-(5-(6-((2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 158) (60 mg, 0.064 mmol) in dioxane (0.5 mL) and thereaction was stirred vigorously for 4 h. The reaction was concentratedto dryness. Then(S)-2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetic acid(Cap-177a) (18.2 mg, 0.084 mmol), DMF (0.5 mL), DIPEA (0.067 mL, 0.39mmol) and finally HATU (32 mg, 0.084 mmol) was added to the crudematerial and the reaction was stirred at rt for 1 h. The reaction waspartially concentrated, diluted with MeOH, filtered and purified bypreparative HPLC (MeOH/water with a TFA buffer) and repurified in oneinjection by Prep HPLC (MeOH/water with an ammonium acetate buffer) toyield methyl((1S)-2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-((3S)-tetrahydro-2H-pyran-3-yl)ethyl)carbamate(30.5 mg) as a white solid. LC-MS retention time 3.376 min; m/z 803.66(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.14 (s, 1H), 7.94 (s, 1H), 7.78-7.86 (m, 3H), 7.49(dd, J=8.5, 1.5 Hz, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 5.15 (ddd, J=12.9,8.7, 4.5 Hz, 2H), 4.57 (d, J=6.8 Hz, 1H), 3.70-3.86 (m, 3H), 3.67 (br.s., 3H), 3.66 (br. s., 3H), 3.58-3.64 (m, 1H), 3.53 (t, J=8.3 Hz, 1H),3.45 (dd, J=11.4, 8.2 Hz, 1H), 2.31-2.57 (m, 4H), 1.93-2.17 (m, 5H),1.67-1.84 (m, 2H), 1.50-1.63 (m, 2H), 1.08-1.17 (m, 2H), 0.98 (d, J=6.8Hz, 3H), 0.92 (d, J=6.8 Hz, 3H), 0.78 (br. s., 2H).

Methyl((1S)-1-(((2S,4S)-2-(4-(6-(4-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (20.99 mg, 0.055 mmol) was added to a solution of an HCl salt of2-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline(Intermediate 164) (16.5 mg, 0.024 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (9.7 mg, 0.055 mmol)in DMF (0.5 mL) and DIPEA (0.038 mL, 0.22 mmol) and the reaction mixturewas stirred at rt for 16 h. The reaction was diluted with MeOH, filteredand purified by preparative HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield a TFA salt of methyl((1S)-1-(((2S,4S)-2-(4-(6-(4-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(8.3 mg, 6.94 μmol, 28.9% yield) as a yellow solid. LC-MS retention time3.555 min; m/z 818.78 (MH+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min, and an analysis time of5 min where Solvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid andSolvent B was 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (400 MHz, MeOD) δ ppm 8.60 (d, J=8.5 Hz, 1H), 8.34 (d, J=1.8 Hz,1H), 8.32 (s, 1H), 8.26-8.31 (m, 1H), 8.21-8.26 (m, 1H), 8.06 (d, J=8.5Hz, 1H), 7.97-8.03 (m, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.93 (s, 1H),7.87-7.92 (m, 2H), 5.19-5.36 (m, 2H), 4.29-4.41 (m, 2H), 4.24 (t, J=6.9Hz, 2H), 3.67 (s, 6H), 3.44 (q, J=11.0 Hz, 2H), 2.62-2.74 (m, 2H),2.46-2.61 (m, 2H), 1.97-2.12 (m, 2H), 1.82-1.97 (m, 2H), 1.26 (dd,J=6.3, 3.3 Hz, 6H), 0.91-0.96 (m, 6H), 0.89 (dd, J=6.7, 5.1 Hz, 6H).

Methyl((1S)-1-(((2S,5S)-2-(4-(6-(4-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (15.74 mg, 0.041 mmol) was added to a solution of a crude HCl saltof2-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline(Intermediate 167) (12.35 mg, 0.018 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (7.25 mg, 0.041 mmol)in DMF (0.5 mL) and DIPEA (0.028 mL, 0.16 mmol) and the reaction mixturewas stirred at rt for 16 h. The reaction was diluted with MeOH, filteredand purified by preparative HPLC (H₂O-MeOH with 0.1% TFA buffer) toyield a TFA salt of methyl((1S)-1-(((2S,5S)-2-(4-(6-(4-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(3.9 mg) as a yellow solid. LC-MS retention time 3.616 min; m/z 818.73(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.68 (d, J=8.8 Hz, 1H), 8.39 (d, J=1.3 Hz, 1H),8.30-8.35 (m, 2H), 8.26-8.31 (m, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.99-8.06(m, 3H), 7.89-7.94 (m, 2H), 5.14-5.31 (m, 2H), 4.14 (dd, J=8.8, 5.0 Hz,2H), 3.68 (s, 6H), 2.47-2.59 (m, 2H), 2.23-2.43 (m, 4H), 1.95-2.10 (m,4H), 1.56 (dd, J=6.7, 3.6 Hz, 6H), 1.01-1.07 (m, 2H), 0.99 (dd, J=6.7,3.4 Hz, 6H), 0.89 (dd, J=6.8, 1.8 Hz, 6H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (50.7 mg, 0.133 mmol) was added to a solution of an HCl salt ofmethyl((1S)-1-(((2S,4S)-2-(4-(6-(4-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(Intermediate 173) (41.7 mg, 0.058 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (23.4 mg, 0.133 mmol)in DMF (1 mL) and DIPEA (0.09 mL, 0.5 mmol) and the reaction mixture wasstirred at rt for 16 h. The reaction was diluted with MeOH, filtered andpurified by preparative HPLC (H₂O-MeOH with 0.1% TFA buffer) to yield aTFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(22.3 mg) as a yellow solid. LC-MS retention time 3.451 min; m/z 815.72(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 9.41 (s, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.41-8.47 (m,1H), 8.28 (d, J=1.3 Hz, 2H), 8.03 (d, J=8.5 Hz, 1H), 8.00-8.07 (m, 1H),7.87-7.95 (m, 3H), 5.10-5.26 (m, 2H), 4.57 (t, J=6.7 Hz, 2H), 3.76-3.89(m, 2H), 3.68 (s, 6H), 2.70 (dd, J=13.7, 9.2 Hz, 2H), 2.44-2.56 (m, 2H),2.14-2.26 (m, 2H), 2.04-2.14 (m, 2H), 1.07-1.16 (m, 2H), 1.02 (dd,J=6.8, 2.0 Hz, 6H), 0.93 (dd, J=6.8, 2.0 Hz, 6H), 0.83-0.99 (m, 2H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (12.24 mg, 0.032 mmol) was added to a solution of an HCl salt ofmethyl((1S)-1-(((2S,4S)-2-(4-(6-(4-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(Intermediate 173) (10.1 mg, 0.014 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(7.0 mg, 0.032 mmol) in DMF (0.5 mL) and DIPEA (0.022 mL, 0.13 mmol) andthe reaction mixture was stirred at rt for 2 h. The reaction was dilutedwith MeOH, filtered and purified by preparative HPLC (H₂O-MeOH with 0.1%TFA buffer) to yield a TFA salt of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinoxalinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(7.3 mg) as a yellow solid. LC-MS retention time 3.251 min; m/z 899.79(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 9.41 (s, 1H), 8.41-8.47 (m, 2H), 8.27-8.31 (m, 2H),8.03 (d, J=8.5 Hz, 1H), 8.01-8.06 (m, 1H), 7.87-7.95 (m, 3H), 5.09-5.26(m, 2H), 4.61 (t, J=7.2 Hz, 2H), 3.90-4.01 (m, 4H), 3.80-3.90 (m, 2H),3.68 (s, 6H), 3.34-3.47 (m, 4H), 2.70 (dd, J=13.6, 9.3 Hz, 2H),2.45-2.57 (m, 2H), 1.99-2.19 (m, 4H), 1.36-1.68 (m, 8H), 1.02-1.16 (m,2H), 0.79-0.96 (m, 2H).

Methyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-((4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

N-Chlorosuccinimide (6.97 mg, 0.052 mmol) was added to a stirredsolution of methyl((1S)-2-((1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(Example 82) (21.0 mg, 0.025 mmol) in DMF and then the reaction vesselwas flushed with a stream of nitrogen, sealed and heated at 50° C. for 3h. Additional N-chlorosuccinimide (5.0 mg) was added and the reactionvessel was flushed with nitrogen, sealed and heated at 50° C. for 3 h,then the reaction was cooled and concentrated under a stream onnitrogen. The remnants were dissolved into MeOH, filtered, and purifiedby preparative HPLC (MeOH/water with TFA buffer) to yield a TFA salt ofmethyl((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-((4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(8.1 mg) as a yellow solid. LC-MS retention time 4.276 min; m/z 457.47(½ MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.18 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=8.8 Hz, 1H),7.93 (d, J=8.5 Hz, 1H), 7.88 (dd, J=8.8, 1.8 Hz, 1H), 7.59 (dd, J=8.5,1.5 Hz, 1H), 5.05 (dd, J=8.5, 6.3 Hz, 1H), 4.99 (t, J=6.9 Hz, 1H), 4.62(d, J=7.5 Hz, 2H), 3.91-3.98 (m, 4H), 3.74-3.81 (m, 1H), 3.68-3.72 (m,1H), 3.67 (s, 6H), 3.34-3.45 (m, 4H), 2.45-2.56 (m, 2H), 2.39-2.44 (m,2H), 1.96-2.11 (m, 4H), 1.37-1.66 (m, 8H), 1.05-1.14 (m, 2H), 0.74-0.84(m, 2H).

Methyl((1S)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamoyl)-2-methylpropyl)carbamate

HATU (77 mg, 0.20 mmol) was added to a stirred solution of an HCl saltof(S)-1-(5-(4-(6-(2-((S)-1-amino-2-methylpropyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-methylpropan-1-amine(Intermediate 178) (57.4 mg, 0.092 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (35.4 mg, 0.202 mmol)and DIPEA (0.096 mL, 0.55 mmol) in DCM (1.5 mL) and the reaction mixturewas stirred at rt for 2 h. The crude reaction mixture was concentratedto dryness and purified by preparative HPLC (TFA buffer) to yield a TFAsalt of methyl((1S)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamoyl)-2-methylpropyl)carbamate(60.4 mg) as a white solid. LC-MS retention time 2.253 min; m/z 759.6(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and SolventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

3-Methyl-N-((1S)-2-methyl-1-(4-(4-(6-(2-((1S)-2-methyl-1-((3-methylbutanoyl)amino)propyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)propyl)butanamide

HATU (119 mg, 0.313 mmol) was added to a stirred solution of an HCl saltof(S)-1-(5-(4-(6-(2-((S)-1-amino-2-methylpropyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-methylpropan-1-amine(Intermediate 178) (89 mg, 0.142 mmol), 3-methylbutanoic acid (32 mg,0.31 mmol) and DIPEA (0.149 mL, 0.855 mmol) in DCM (2 mL) and thereaction mixture was stirred at rt for 2 h. The crude reaction mixturewas concentrated to dryness and purified twice by preparative HPLC (TFAbuffer) to yield a TFA salt of3-methyl-N-((1S)-2-methyl-1-(4-(4-(6-(2-((1S)-2-methyl-1-((3-methylbutanoyl)amino)propyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)propyl)butanamide(54.6 mg) as a beige solid. LC-MS retention time 2.375 min; m/z 645.6(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and SolventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode.

2-((2S,5S)-1-Acetyl-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-1-acetyl-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole

HATU (63.2 mg, 0.166 mmol) was added to a solution of2-(((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 117) (contaminated with ammonium acetate) (38 mg, 0.076mmol) and(S)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)aceticacid (40.8 mg, 0.166 mmol) in DMF (1.0 mL) and DIPEA (0.053 mL, 0.30mmol) and the reaction was at rt overnight. The reaction mixture wasdiluted with MeOH, filtered and purified by preparative HPLC (MeOH/waterwith a TFA buffer) to yield a TFA salt of2-((2S,5S)-1-acetyl-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-1-acetyl-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(20 mg) as a yellow solid. LC-MS retention time 3.123 min; m/z 587.62(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.30 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.8 Hz, 1H),8.09 (d, J=8.8 Hz, 1H), 7.93-8.01 (m, 4H), 7.84-7.91 (m, 4H), 5.25 (q,J=8.4 Hz, 2H), 4.31-4.40 (m, 2H), 2.53-2.66 (m, 2H), 2.28-2.40 (m, 4H),2.25 (s, 3H), 2.25 (s, 3H), 1.88-1.97 (m, 2H), 1.47 (dd, J=6.5, 3.5 Hz,6H), 1.14-1.19 (m, 1H).

Methyl(1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)((methoxycarbonyl)amino)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate

HATU (61.9 mg, 0.163 mmol) was added to a solution of an HCl salt of2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 117) (48 mg, 0.074 mmol) and2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)aceticacid (Cap-179 stereoisomer 2) (39.9 mg, 0.163 mmol) in DMF (0.8 mL) andDIPEA (0.09 mL, 0.52 mmol) and the reaction was stirred rt for 2 h. Thereaction was diluted with MeOH, filtered and purified in two injectionsby prep HPLC (MeOH/water with TFA buffer) to yield a TFA salt of methyl(1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-42S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)((methoxycarbonyl)amino)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate(55.5 mg) as a light yellow solid. LC-MS retention time 3.506 min; m/z479.54 (½ MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. The ¹H NMRpresented as a complex mixture of rotamers.

Methyl((1S)-2-((2S,4S)-2-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (23.99 mg, 0.063 mmol) was added to a solution of an HCl salt of(1R,3S,5R)-3-(4-((6-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 175) (15 mg, 0.025 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(13.70 mg, 0.063 mmol) in DMF (0.4 mL) and DIPEA (0.03 mL, 0.2 mmol) andthe reaction was stirred at rt for 1.5 h. The reaction was diluted withMeOH, filtered and purified in two injections by preparative HPLC(MeOH/water with TFA buffer) to a TFA salt of methyl((1S)-2-((2S,4S)-2-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(12.0 mg) as a yellow solid. LC-MS retention time 3.040 min; m/z 847.76(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.28 (s, 1H), 8.18 (s, 1H), 8.05 (d, J=8.8 Hz, 1H),7.97-8.02 (m, 2H), 7.88 (dd, J=8.8, 1.8 Hz, 1H), 7.76 (s, 1H), 7.67 (dd,J=8.4, 1.4 Hz, 1H), 5.23 (dd, J=10.9, 6.9 Hz, 1H), 5.09 (dd, J=9.0, 6.5Hz, 1H), 4.59 (d, J=7.8 Hz, 1H), 4.34-4.41 (m, 1H), 4.28 (d, J=8.0 Hz,1H), 3.86-4.00 (m, 4H), 3.75-3.81 (m, 1H), 3.67 (s, 3H), 3.67 (s, 3H),3.32-3.50 (m, 5H), 2.39-2.74 (m, 4H), 1.87-2.13 (m, 4H), 1.27-1.65 (m,8H), 1.25 (d, J=6.3 Hz, 3H), 1.04-1.14 (m, 1H), 0.86 (br. s., 1H).

Methyl((1S)-1-(((2S,4S)-2-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (60.8 mg, 0.160 mmol) was added to a solution of an HCl salt of(1R,3S,5R)-3-(4-((6-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 175) (38 mg, 0.064 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (28.0 mg, 0.160 mmol)in DMF (0.7 mL) and DIPEA (0.08 mL, 0.4 mmol) and stirred at rt for 1.5h. The reaction was diluted with MeOH, filtered and purified twice bypreparative HPLC (MeOH/water with TFA buffer) to yield a TFA salt methyl((1S)-1-(((2S,4S)-2-(4-(6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(19.1 mg) as an off-white solid. LC-MS retention 3.288 time min; m/z763.74 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.28 (s, 1H), 8.18 (s, 1H), 8.05 (d, J=8.8 Hz, 1H),7.98-8.03 (m, 2H), 7.88 (dd, J=8.7, 1.6 Hz, 1H), 7.76 (s, 1H), 7.67 (dd,J=8.5, 1.5 Hz, 1H), 5.24 (dd, J=10.9, 7.2 Hz, 1H), 5.10 (dd, J=9.0, 6.5Hz, 1H), 4.55 (d, J=6.5 Hz, 1H), 4.30-4.37 (m, 1H), 4.23 (d, J=7.3 Hz,1H), 3.72-3.79 (m, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.43 (t, J=10.4 Hz,1H), 2.49-2.74 (m, 3H), 2.44 (ddd, J=13.6, 6.7, 6.4 Hz, 1H), 2.11-2.22(m, 1H), 1.98-2.11 (m, 2H), 1.89 (q, J=12.0 Hz, 1H), 1.25 (d, J=6.3 Hz,3H), 1.06-1.15 (m, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.95-0.98 (m, 1H), 0.94(d, J=4.0 Hz, 3H), 0.92 (d, J=3.8 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H).

2-((2S,4S)-4-Methyl-1-(3-methylbutanoyl)-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-1-(3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole

HATU (76 mg, 0.200 mmol) was added to a solution of an HCl salt of2-((2S,4S)-4-methylpyrrolidin-2-yl)-5-(4-(6-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole(Intermediate 196) (64.8 mg, 0.1 mmol), 3-methylbutanoic acid (22.5 mg,0.220 mmol) and DIPEA (0.122 mL, 0.700 mmol) in DCM (2 mL) and themixture was stirred rt overnight. The reaction mixture was evaporated todryness and then purified by preparative HPLC to afford a TFA salt of2-((2S,4S)-4-methyl-1-(3-methylbutanoyl)-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-1-(3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(61.7 mg) as an off-white solid. LC-MS retention time 1.853 min; m/z671.64 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 1 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-2-((2S,4S)-2-(4-(6-(4-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (12.75 mg, 0.034 mmol) was added to a solution of2-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline(Intermediate 164) (10 mg, 0.015 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(7.28 mg, 0.034 mmol) in DMF (0.5 mL) and DIPEA (0.023 mL, 0.13 mmol)and the mixture was stirred at rt for 16 h. The reaction wasconcentrated and the residue was purified by preparative HPLC (H₂O-MeOHwith 0.1% TFA buffer) to yield a TFA salt of methyl((1S)-2-((2S,4S)-2-(4-(6-(4-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(8.6 mg) as a yellow solid. LC-MS retention time 3.243 min; m/z 902.90(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.61 (d, J=8.8 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H),8.22-8.33 (m, 3H), 8.07 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H),7.97-8.04 (m, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.85-7.95 (m, 2H), 5.17-5.33(m, 2H), 4.32-4.45 (m, 2H), 4.28 (dd, J=8.2, 5.4 Hz, 2H), 3.83-3.98 (m,4H), 3.67 (s, 6H), 3.22-3.54 (m, 6H), 2.63-2.75 (m, 2H), 2.46-2.61 (m,2H), 1.83-2.04 (m, 4H), 1.52-1.64 (m, 2H), 1.30-1.53 (m, 6H), 1.26 (dd,J=6.3, 4.0 Hz, 6H).

Methyl((1S)-1-(((3R)-3-(4-(4-(6-(2-((3R)-4-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-3-morpholinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-morpholinyl)carbonyl)-2-methylpropyl)carbamate

HATU (96 mg, 0.252 mmol) was added to a solution of an HCl salt of(R)-3-(5-(4-(6-(2-((R)-morpholin-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)morpholine(Intermediate 181) (71.6 mg, 0.110 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (44.2 mg, 0.252 mmol)in DMF (1.0 mL) and DIPEA (0.13 mL, 0.77 mmol) and the reaction mixturewas flushed with nitrogen, sealed and stirred at rt for 3 h. Thereaction was concentrated under a stream of nitrogen overnight, dilutedwith MeOH (˜5 mL), filtered and purified by preparative HPLC (MeOH/waterwith a TFA buffer) to yield a TFA salt of methyl((1S)-1-(43R)-3-(4-(4-(6-(2-43R)-4-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-3-morpholinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-morpholinyl)carbonyl)-2-methylpropyl)carbamate(75.5 mg) as a off-white solid LC-MS retention time 3.351 min; m/z822.07 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR presentsas a mixture of rotamers. ¹H NMR (400 MHz, MeOD) δ ppm 8.47 (s, 0.5H),8.33 (s, 0.5H), 8.27 (s, 1H), 7.85-8.17 (m, 10H), 5.95 (d, J=4.5 Hz,2H), 4.71 (dd, J=12.5, 7.8 Hz, 1H), 4.35-4.58 (m, 4H), 3.94-4.20 (m,5H), 3.79 (s, 3H), 3.68 (s, 3H), 3.53-3.78 (m, 3H), 2.76-2.91 (m, 1H),2.12 (br. s., 2H), 1.05-1.19 (m, 6H), 0.81-1.00 (m, 6H).

Methyl((1S)-2-((3R)-3-(4-(4-(6-(2-((3R)-4-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-3-morpholinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-morpholinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (88 mg, 0.231 mmol) was added to a solution of an HCl salt of(R)-3-(5-(4-(6-(2-((R)-morpholin-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)morpholine(Intermediate 181) (65.5 mg, 0.100 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(50.2 mg, 0.231 mmol) in DMF (1.0 mL) and DIPEA (0.12 mL, 0.70 mmol) andthe reaction mixture was flushed with nitrogen, sealed and stirred at rtfor 3 h. The reaction was concentrated under a stream of nitrogenovernight, diluted with MeOH (˜5 mL), filtered and purified bypreparative HPLC (MeOH/water with a TFA buffer) to yield a TFA salt ofmethyl((1S)-2-((3R)-3-(4-(4-(6-(2-((3R)-4-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-3-morpholinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-morpholinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(75 mg) as an off-white solid. LC-MS retention time 3.120 min; m/z906.15 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

(1R,3S,5R)-2-(3-Methylbutanoyl)-3-(4-(6-((2-((1R,3S,5R)-2-(3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane

HATU (74.8 mg, 0.197 mmol) was added to a stirred solution of an HClsalt of(1R,3S,5R)-3-(5-(6-((2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 124) (64.7 mg, 0.098 mmol), 3-methylbutanoic acid (22.09mg, 0.216 mmol) and DIPEA (0.103 mL, 0.590 mmol) in DCM (1.5 mL) and thereaction mixture was stirred at rt for 2-3 h. The reaction wasconcentrated to dryness and purified by preparative HPLC (TFA buffer) toyield a TFA salt of(1R,3S,5R)-2-(3-methylbutanoyl)-3-(4-(6-((2-((1R,3S,5R)-2-(3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(51.5 mg) as a beige solidified foam. LC-MS retention time 1.775 min;m/z 615.41 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×30 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 1 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode.

Methyl((1S)-1-(((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-piperidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-piperidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (93 mg, 0.245 mmol) was added to a solution of an HCl salt of(S)-2-(5-(4-(6-(2-((S)-piperidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)piperidine(Intermediate 184) (69.0 mg, 0.106 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (42.9 mg, 0.245 mmol)in DMF (1.0 mL) and DIPEA (0.13 mL, 0.75 mmol) and the reaction wasflushed with nitrogen, sealed and stirred at rt for 1 h. The reactionwas concentrated under a stream of nitrogen overnight, diluted with MeOH(˜5 mL), filtered and purified by preparative HPLC (MeOH/water with aTFA buffer) to yield a TFA salt of methyl((1S)-1-(((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-piperidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-piperidinyl)carbonyl)-2-methylpropyl)carbamate(88.9 mg) as a light yellow solid. LC-MS retention time 3.530 min; m/z818.08 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR presentsas a mixture of rotamers. ¹H NMR (400 MHz, MeOD) δ ppm 8.46 (s, 0.65H),8.33 (br. s., 0.35H), 8.27 (s, 1H), 7.84-8.15 (m, 10H), 6.05 (br. s.,1.3H), 5.80-5.90 (m, 0.7H), 4.67-4.78 (m, 1.3H), 4.42-4.50 (m, 2H),3.99-4.10 (m, 0.7H), 3.78 (br. s., 3.5H), 3.69 (br. s., 2.5H), 3.40-3.52(m, 0.7H), 2.61-2.73 (m, 1.3H), 2.46-2.59 (m, 1.3H), 2.37 (br. s.,0.7H), 2.03-2.24 (m, 4H), 1.91-2.02 (m, 1.3H), 1.63-1.88 (m, 5.4H),1.45-1.62 (m, 1.4H), 1.11 (t, J=6.8 Hz, 7.3H), 0.93-1.03 (m, 4.7H).

Methyl((1S)-2-((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-piperidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-piperidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (84 mg, 0.222 mmol) was added to a solution of an HCl salt of(S)-2-(5-(4-(6-(2-((S)-piperidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)piperidine(Intermediate 184) (62.5 mg, 0.096 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(48.2 mg, 0.222 mmol) in DMF (1.0 mL) and DIPEA (0.12 mL, 0.68 mmol) andthe reaction was flushed with nitrogen, sealed and stirred at rt for 1h. The reaction was concentrated under a stream of nitrogen overnight,diluted with MeOH (˜5 mL), filtered and purified by preparative HPLC(MeOH/water with a TFA buffer) to yield a TFA salt of methyl((1S)-2-((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-piperidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-piperidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(71.2 mg) as a light yellow solid. LC-MS retention time 3.348 min; m/z902.10 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR presentsas a mixture of rotamers. ¹H NMR (400 MHz, MeOD) δ ppm 8.45 (s, 0.6H),8.32 (br. s., 0.4H), 8.27 (s, 1H), 8.02-8.15 (m, 4.4H), 7.85-8.02 (m,5.6H), 6.08 (br. s., 1.2H), 5.90 (br. s., 0.8H), 4.70 (br. s., 1.2H),4.45-4.59 (m, 2H), 3.90-4.10 (m, 4.8H), 3.77 (s, 3.6H), 3.69 (br. s.,2.4H), 3.36-3.50 (m, 5H), 2.35-2.73 (m, 3H), 1.36-2.22 (m, 20H).

Methyl((1S)-1-(((2S,5R)-2-(4-(4-(6-(2-((2S,5R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (62.0 mg, 0.163 mmol) was added to a solution of an HCl salt of2-((2S,5R)-5-methylpyrrolidin-2-yl)-5-(4-(6-(2-((2S,5R)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazole(Intermediate 187) (46 mg, 0.071 mmol) and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (28.6 mg, 0.163 mmol)DMF (0.7 mL) and DIPEA (0.09 mL, 0.5 mmol) and the reaction vessel wasflushed with nitrogen, sealed and stirred at rt for 1 h. The reactionwas concentrated under a stream of nitrogen overnight, diluted with MeOH(˜3 mL), filtered and purified by preparative HPLC (MeOH/water with aTFA buffer) to yield a TFA salt of methyl((1S)-1-(((2S,5R)-2-(4-(4-(6-(2-((2S,5R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(53.3 mg) as a light yellow solid. LC-MS retention time 3.255 min; m/z818.08 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR presentsas a complex mixture of rotamers. ¹H NMR (400 MHz, MeOD) δ ppm 8.31 (s,0.5H), 8.26-8.30 (m, 1.5H), 8.13 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.5 Hz,1H), 7.93-8.00 (m, 4H), 7.83-7.93 (m, 4H), 5.67 (t, J=7.8 Hz, 0.7H),5.38-5.45 (m, 1.3H), 4.44-4.68 (m, 3.3H), 3.92 (dd, J=8.2, 4.4 Hz,0.7H), 3.66 (s, 3.5H), 3.41 (s, 1H), 3.35 (s, 1.5H), 2.53-2.92 (m,3.3H), 1.96-2.30 (m, 6H), 1.78-1.87 (m, 0.7H), 1.43-1.53 (m, 3.5H), 1.33(dd, J=6.3, 2.5 Hz, 2.5H), 0.98-1.06 (m, 6H), 0.96 (d, J=6.8 Hz, 2.4H),0.84 (d, J=6.8 Hz, 3.6H).

Methyl((1S)-2-((2S,5R)-2-(4-(4-(6-(2-((2S,5R)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (55.8 mg, 0.147 mmol) was added to a solution of vial an HCl saltof2-((2S,5R)-5-methylpyrrolidin-2-yl)-5-(4-(6-(2-((2S,5R)-5-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazole(Intermediate 187) (41.4 mg, 0.064 mmol) and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(31.9 mg, 0.147 mmol) in DMF (0.7 mL) and DIPEA (0.08 mL, 0.4 mmol) andthe reaction vessel was flushed with nitrogen, sealed and stirred at rtfor 1 h. The reaction was concentrated under a stream of nitrogenovernight, diluted with MeOH (˜3 mL), filtered and purified bypreparative HPLC (MeOH/water with a TFA buffer) to yield a TFA salt ofmethyl((1S)-2-((2S,5R)-2-(4-(4-(6-(2-((2S,5R)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(27.6 mg) as a light yellow solid LC-MS retention time 3.135 min; m/z902.15 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. Mixture ofrotamers by ¹H NMR. ¹H NMR (400 MHz, MeOD) δ ppm 8.31 (s, 0.5H),8.25-8.29 (m, 1.5H), 8.13 (d, J=8.8 Hz, 1H), 8.08 (dd, J=8.8, 2.5 Hz,1H), 7.93-8.00 (m, 4H), 7.82-7.92 (m, 4H), 5.71 (t, J=7.9 Hz, 0.8H),5.37-5.45 (m, 1.2H), 4.47-4.69 (m, 3H), 3.89-4.07 (m, 5H), 3.67 (s, 3H),3.24-3.43 (m, 7H), 2.57-2.92 (m, 3H), 1.96-2.29 (m, 6H), 1.79-1.87 (m,1H), 1.35-1.67 (m, 11H), 1.33 (dd, J=6.5, 2.5 Hz, 3H).

Methyl((1S)-1-(((2S)-2-(4-(6-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methylene-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (102 mg, 0.269 mmol) was added to a stirred solution of the tetraHCl salt of2-((S)-4-methylenepyrrolidin-2-yl)-4-(4-(6-(2-((S)-4-methylenepyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazole(Intermediate 189) (86 mg, 0.148 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (47.1 mg, 0.269mmol), and Hunig's base (0.234 mL, 1.34 mmol) in DMF (6 mL). Thereaction was stirred 4 h at room temperature and purified by preparativeHPLC (MeOH/water with 0.1% TFA) to afford a bis TFA salt of methyl((1S)-1-(((2S)-2-(4-(6-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methylene-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(65 mg, 46%). LC-MS retention time 3.22 min; calcd. for C₄₆H₅₃N₈O₆:813.40 Found m/z 813.7 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeCN/95% water/10 mM NH₄OAc and Solvent B was95% MeCN/5% water/10 mM NH₄OAc. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500MHz, MeOD) δ ppm 8.29 (s, 1H), 8.28 (s, 1H), 8.15 (d, J=8.9 Hz, 1H),8.09 (d, J=8.9 Hz, 1H), 8.0-7.85 (m, 8H), 5.50-5.45 (m, 2H), 5.32 (s,2H), 5.28 (s, 2H), 4.72 (d, J=11.6 Hz, 2H), 4.60 (dd, J=11.3, 3.4 Hz,2H), 4.21 (dd, J=7.6, 2.8 Hz, 2H), 3.68 (s, 6H), 2.98-2.92 (m, 2H),2.10-2.06 (m, 2H), 1.06-1.02 (m, 2H), 0.97-0.94 (m, 12H).

Methyl((1S)-2-((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methylene-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (102 mg, 0.269 mmol) was added to a stirred solution of the tetraHCl salt of2-((S)-4-methylenepyrrolidin-2-yl)-4-(4-(6-(2-((S)-4-methylenepyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazole(Intermediate 189) (86 mg, 0.148 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(58.4 mg, 0.269 mmol), and Hunig's base (0.234 mL, 1.34 mmol) in DMF (6mL). The reaction was stirred 5 h at room temperature and purified bypreparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt ofmethyl((1S)-2-((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methylene-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate.LC-MS retention time 2.81 min; calcd. for C₅₀H₅₇N₈O₈: 897.43 Found m/z897.41 [M+H]⁺. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min and an analysis time of 5 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.29 (s,2H), 8.4 (d, J=8.8 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.01-7.85 (m, 8H),5.50-5.44 (m, 2H), 5.32 (s, 2H), 5.28 (s, 2H), 4.75 (d, J=14.6 Hz, 2H),4.63 (dd, J=13.3, 4.5 Hz, 2H), 4.27 (dd, J=8.3, 3.5 Hz, 2H), 3.99-3.91(m, 4H) 3.69 (s, 6H), 3.41-3.37 (m 4H), 3.0-2.94 (m, 2H), 2.02-1.98 (m,2H), 1.68-1.65 (m, 2H), 1.59-1.32 (m, 8H).

Methyl((1S)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)carbamoyl)-2-methylpropyl)carbamate

HATU (149 mg, 0.393 mmol) was added to a stirred solution of the tetraHCl salt of(S)-1-(4-(4-(6-(2-((S)-1-aminoethyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)ethanamine(Intermediate 191) (111 mg, 0.148 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (47.1 mg, 0.196mmol), and Hunig's base (0.343 mL, 1.96 mmol) in DMF (8 mL). Thereaction was stirred 4 h at room temperature and purified by preparativeHPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt methyl((1S)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)carbamoyl)-2-methylpropyl)carbamate(91 mg, 47%). LC-MS retention time 2.96 min; calcd. for C₄₀H₄₉N₈O₆:737.38 Found m/z 737.45 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.35 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.9 Hz, 1H), 8.09 (d, J=8.9Hz, 1H), 7.99-7.88 (m, 8H), 5.30-5.27 (m, 2H), 3.99-3.97 (m, 2H), 3.70(s, 6H), 2.14 (br. s, 2H), 1.78-1.75 (m, 6H), 0.99-0.95 (m, 12H).

Methyl((1S)-2-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (149 mg, 0.393 mmol) was added to a stirred solution of the tetraHCl salt of(S)-1-(4-(4-(6-(2-((S)-1-Aminoethyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)ethanamine(Intermediate 191) (83 mg, 0.196 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (85mg, 0.393 mmol), and Hunig's base (0.343 mL, 1.96 mmol) in DMF (8 mL).The reaction was stirred 5 h at room temperature and purified bypreparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt ofmethyl((1S)-2-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(89 mg, 42%). LC-MS retention time 2.64 min; calcd. for C₄₄H₅₃N₈O₈:821.40 Found m/z 821.80 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% AcCN/95% water/10 mM NH₄OAc and Solvent B was95% AcCN/5% water/10 mM NH₄OAc. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500MHz, MeOD) δ ppm 8.34 (s, 1H), 8.2 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.09(d, J=8.6 Hz, 1H), 7.99-7.87 (m, 8H), 5.29-5.26 (m, 2H), 4.02-4.00 (m,2H), 3.98-3.93 (m, 4H) 3.71 (s, 6H), 3.41-3.37 (m 4H), 2.02 (br. s, 2H),1.79-1.76 (m, 6H), 1.62 (d, J=13.0 Hz, 2H), 1.49-1.39 (m, 6H).

Methyl((1S)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)(methyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)(methyl)carbamoyl)-2-methylpropyl)carbamate

HATU (84 mg, 0.222 mmol) was added to a stirred solution of the tetraHCl salt of(S)—N-Methyl-1-(4-(4-(6-(2-((S)-1-(methylamino)ethyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)ethanamine(Intermediate 193) (66 mg, 0.111 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (38.9 mg, 0.222mmol), and Hunig's base (0.194 mL, 1.11 mmol) in DMF (5 mL). Thereaction was stirred 5 h at room temperature and purified by preparativeHPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt of methyl((1S)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)(methyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)(methyl)carbamoyl)-2-methylpropyl)carbamate.LC-MS retention time 1.78 min; calcd. for C₄₂H₅₃N₈O₆: 765.41. Found m/z765.41 [M+H]⁺. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped a PHENOMENEX® Luna C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min and an analysis time of 3 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt; rotamers, 500 MHz, MeOD) δppm 8.44/8.34 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.10-7.88(m, 9H), 6.17-6.14/5.33-5.30 (m, 2H), 4.64-4.6/4.41-4.39 (m, 2H),3.84/3.66 (s, 3H), 3.83/3.59 (s, 3H), 3.37 (s, 6H), 2.10-2.05 (m, 2H),1.90-1.87/1.85-1.82 (m, 6H), 1.15-0.90 (m, 12H).

Methyl((1S)-2-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)(methyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)(methyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (84 mg, 0.222 mmol) was added to a stirred solution of the tetraHCl salt of(S)—N-Methyl-1-(4-(4-(6-(2-((S)-1-(methylamino)ethyl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)ethanamine(Intermediate 193) (66 mg, 0.111 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (48mg, 0.222 mmol), and Hunig's base (0.194 mL, 1.11 mmol) in DMF (5 mL).The reaction was stirred 5 h at room temperature and purified bypreparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt ofMethyl((1S)-2-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)(methyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)(methyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate.LC-MS retention time 1.58 min; calcd. for C₄₆H₅₇N₈O₈: 849.43 Found m/z849.46 [M+H]⁺. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped a PHENOMENEX® Luna C18 2.0×30 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 1 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 2 min, a hold time of 1 min and an analysis time of 3 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt, rotamers 500 MHz, MeOD) δ ppm8.45/8.34 (s, 1H), 8.28 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.09 (d, J=8.3Hz, 1H), 8.06-7.88 (m, 8H), 6.21-6.18/5.38-5.34 (m, 2H),4.73-4.70/4.47-4.45 (m, 2H), 4.02-3.94 (m, 4H) 3.84/3.63 (s, 3H),3.83/3.60 (s, 3H), 3.46-3.38 (m 4H), 3.37/3.35 (s, 6H), 2.02 (br. s,2H), 1.91-1.88/1.84-1.81 (m, 6H), 1.68 (d, J=13.0 Hz, 2H), 1.53-1.42 (m,6H).

Methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (32 mg, 0.085 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4S)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 196) (25 mg, 0.039 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14.9 mg, 0.085mmol), and Hunig's base (0.054 mL, 0.308 mmol) in DMF (1 mL). Thereaction was stirred 1 h at room temperature and partially concentratedby purge of nitrogen gas. The residue was taken up in MeOH and purifiedby preparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA saltof methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(24.5 mg, 57.8%). LC-MS retention time 3.05 min; calcd. for C₄₆H₅₇N₈O₆:817.44 Found m/z 817.36 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.29 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.08 (d, J=8.6Hz, 1H), 7.99-7.85 (m, 8H), 5.27-5.22 (m, 2H), 4.37-4.33 (m, 2H),4.25-4.23 (m, 2H), 3.68 (s, 6H), 3.47-3.41 (m, 2H), 2.72-2.68 (m 2H),2.55 (br. s, 2H), 2.07-2.03 (m, 2H), 1.92-1.87 (m, 2H), 1.27-1.26 (m,6H), 0.95-0.9 (m, 12H).

Methyl(2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(((methoxycarbonyl)amino)(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (64.5 mg, 0.170 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4S)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 196) (50 mg, 0.077 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(36.8 mg, 0.170 mmol), and Hunig's base (0.11 mL, 0.617 mmol) in DMF (1mL). The reaction was stirred 1 h at room temperature and partiallyconcentrated by purge of nitrogen gas. The residue was taken up in MeOHand purified by preparative HPLC (MeCN/water with 0.1% TFA) to afford abis TFA salt of methyl(2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(((methoxycarbonyl)amino)(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate.LC-MS retention time 2.84 min; calcd. for C₅₀H₆₁N₈O₈: 901.46 Found m/z901.42 [M+H]⁺. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min and an analysis time of 5 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.29 (s,1H), 8.28 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H),8.00-7.85 (m, 8H), 5.25-5.21 (m, 2H), 4.42-4.39 (m, 2H), 4.30-4.27 (m,2H), 3.96-3.92 (m, 4H), 3.68 (s, 6H), 3.49-3.35 (m 6H), 2.71-2.38 (m,2H), 2.58-2.54 (m, 2H), 1.97-1.89 (m, 4H), 1.60 (d, J=13.0 Hz, 2H),1.48-1.26 (m, 12H).

Methyl(1-cyclopropyl-2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(cyclopropyl((methoxycarbonyl)amino)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate

HATU (39 mg, 0.102 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4S)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 196) (30 mg, 0.085 mmol),(S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid (17.62 mg, 0.102mmol), and Hunig's base (0.065 mL, 0.37 mmol) in DMF (1 mL). Thereaction was stirred 1 h at room temperature and partially concentratedby purge of nitrogen gas. The residue was taken up in MeOH and purifiedby preparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA saltof methyl(1-cyclopropyl-2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(cyclopropyl((methoxycarbonyl)amino)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate(24.5 mg, 57.8%). LC-MS retention time 3.08 min; calcd. for C₄₆H₅₃N₈O₆:813.41 Found m/z 813.45 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.32 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.08 (d, J=8.6Hz, 1H), 7.99-7.87 (m, 8H), 5.29-5.24 (m, 2H), 4.30 (br. s, 2H),3.82-3.80 (m, 2H), 3.68 (s, 6H), 3.43-3.37 (m, 2H), 2.72-2.68 (m 2H),2.55 (br. s, 2H), 1.91-1.86 (m, 2H), 1.25-1.24 (m, 6H), 1.11 (br. s,2H), 0.60-0.58 (m, 4H), 0.53-0.51 (m, 2H), 0.04-0.38 (m, 2H).

Methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)butanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)propyl)carbamate

HATU (45 mg, 0.119 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4S)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 196) (35 mg, 0.054 mmol),(S)-2-(methoxycarbonylamino)butanoic acid (19.14 mg, 0.119 mmol), andHunig's base (0.075 mL, 0.432 mmol) in DMF (1 mL). The reaction wasstirred 1 h at room temperature and partially concentrated by purge ofnitrogen gas. The residue was taken up in MeOH and purified bypreparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt ofmethyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)butanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)propyl)carbamate (36.4 mg, 61.7%). LC-MS retention time 2.91 min; calcd.for C₄₄H₅₃N₈O₆: 789.41 Found m/z 789.41 [M+H]⁺. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C182.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% MeOH/95% water/0.1% TFAand Solvent B was 95% MeOH/5% water/0.1% TFA. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFAsalt, 500 MHz, MeOD) δ ppm 8.30 (s, 1H), 8.28 (s, 1H), 8.14 (d, J=8.6Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.00-7.86 (m, 8H), 5.27-5.22 (m, 2H),4.37 (br. s, 2H), 4.24-4.23 (m, 2H), 3.67 (s, 6H), 3.44-3.39 (m, 2H),2.72-2.68 (m 2H), 2.58 (br. s, 2H), 1.88-1.84 (m, 2H), 1.47-1.25 (m,6H), 0.98-0.92 (m, 10H).

Methyl((1S)-1-cyclobutyl-2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-cyclobutyl-2-((methoxycarbonyl)amino)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate

HATU (45 mg, 0.119 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4S)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 196) (35 mg, 0.054 mmol),(S)-2-cyclobutyl-2-(methoxycarbonylamino)acetic acid (22.23 mg, 0.119mmol) (prepared in a similar manner as Cap-51 using commerciallyavailable (S)-2-(tert-butoxycarbonylamino)-2-cyclobutylacetic acid as astarting material) and Hunig's base (0.075 mL, 0.432 mmol) in DMF (1mL). The reaction was stirred 1 h at room temperature and partiallyconcentrated by purge of nitrogen gas. The residue was taken up in MeOHand purified by preparative HPLC (MeCN/water with 0.1% TFA) to afford abis TFA salt of methyl((1S)-1-cyclobutyl-2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-cyclobutyl-2-((methoxycarbonyl)amino)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate(25.6 mg, 43.6%). LC-MS retention time 3.13 min; calcd. for C₄₈H₅₇N₈O₆:841.44 Found m/z 841.48 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.30 (s, 1H), 8.28 (s, 1H), 8.14 (d, J=8.9 Hz, 1H), 8.09 (d, J=8.6Hz, 1H), 8.00-7.86 (m, 8H), 5.26-5.21 (m, 2H), 4.41-4.37 (m, 4H), 3.68(s, 6H), 3.48-3.43 (m, 2H), 2.71-2.66 (m 4H), 2.56 (br. s, 2H),1.96-1.87 (m, 14H), 1.27-1.26 (m, 6H).

Methyl((1S)-2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-1-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate

HATU (32 mg, 0.085 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4S)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 196) (25 mg, 0.039 mmol),2-(methoxycarbonylamino)-2-((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)aceticacid (Cap-178, stereoisomer 1) (19.61 mg, 0.085 mmol) and Hunig's base(0.054 mL, 0.308 mmol) in DMF (1 mL). The reaction was stirred 1 h atroom temperature and partially concentrated by purge of nitrogen gas.The residue was taken up in MeOH and purified by preparative HPLC(MeCN/water with 0.1% TFA) to afford a bis TFA salt of methyl((1S)-2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-1-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate(21.3 mg, 45.2%). LC-MS retention time 2.94 min; calcd. for C₅₂H₆₄N₈O₈:929.49 Found m/z 929.64 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.32 (s, 1H), 8.28 (s, 1H), 8.15-8.12 (m, 1H), 8.09-8.06 (m, 1H),8.02-7.94 (m, 5H), 7.90-7.86 (m, 3H), 5.28-5.23 (m, 2H), 4.50-4.48 (m,2H), 4.44 (br. s, 2H), 3.95-3.91 (m, 2H), 3.71-3.68 (s, 10H), 3.46-3.41(m, 2H), 2.72-2.67 (m, 2H), 2.55-2.52 (m, 2H), 2.19 (br. s, 2H),1.97-1.92 (m, 2H), 1.60 (br. s, 2H), 1.48-1.46 (m, 2H), 1.39 (br. s,2H), 1.30-1.26 (m, 8H), 1.14-1.10 (m, 6H).

Methyl((1S)-1-(((2S,4R)-2-(4-(4-(6-(2-((2S,4R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (65 mg, 0.171 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4R)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4R)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 201) (50 mg, 0.077 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (30 mg, 0.170 mmol),and Hunig's base (0.108 mL, 0.308 mmol) in DMF (1 mL). The reaction wasstirred 1 h at room temperature and partially concentrated by purge ofnitrogen gas. The residue was taken up in MeOH and purified bypreparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt ofmethyl((1S)-1-(((2S,4R)-2-(4-(4-(6-(2-((2S,4R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(60.7 mg, 71%). LC-MS retention time 3.12 min; calcd. for C₄₆H₅₇N₈O₆:817.44 Found m/z 817.46 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.30 (s, 1H), 8.28 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.09 (d, J=8.6Hz, 1H), 8.00-7.86 (m, 8H), 5.43-5.38 (m, 2H), 4.26-4.24 (m, 2H),4.09-4.05 (m, 2H), 3.69 (s, 6H), 3.64 (br. s, 2H), 2.76-2.73 (m 2H),235-2.32 (m, 2H), 2.25-2.22 (m, 2H), 2.11-2.09 (m, 2H), 1.22-1.20 (m,6H), 0.98-0.93 (m, 12H).

Methyl((1S)-1-(((1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (65 mg, 0.171 mmol) was added to a stirred solution of the tetraHCl salt of(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 203) (50 mg, 0.078 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (30 mg, 0.111 mmol),and Hunig's base (0.108 mL, 0.621 mmol) in DMF (1 mL). The reaction wasstirred 1 h at room temperature and partially concentrated by purge ofnitrogen gas. The residue was taken up in MeOH and purified bypreparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt ofmethyl ((1S)-1-(((1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(54 mg, 63%). LC-MS retention time 3.15 min; calcd. for C₄₆H₅₃N₈O₆:813.41 Found m/z 813.45 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.33 (s, 1H), 8.26 (s, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.07 (d, J=8.6Hz, 1H), 7.98-7.86 (m, 8H), 5.80-5.74 (m, 2H), 4.36-4.34 (m, 2H),4.02-3.99 (m, 2H), 3.73 (s, 6H), 2.99-2.95 (m, 2H), 2.28-2.25 (m 2H),2.16 (br. s, 2H), 2.04 (br.s, 2H), 1.24-1.20 (m, 2H), 1.08 (br. s, 2H),1.02-1.00 (m, 12H).

Methyl((1S)-1-(((1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (62 mg, 0.164 mmol) was added to a stirred solution of the tetraHCl salt of(1S,3S,5S)-5-methyl-3-(4-(4-(6-(2-((1S,3S,5S)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane(Intermediate 209) (50 mg, 0.074 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (28.7 mg, 0.164mmol), and Hunig's base (0.104 mL, 0.595 mmol) in DMF (1 mL). Thereaction was stirred 1 h at room temperature and partially concentratedby purge of nitrogen gas. The residue was taken up in MeOH and purifiedby preparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA saltof Methyl ((1S)-1-(((1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(45 mg, 54%). LC-MS retention time 3.15 min; calcd. for C₄₈H₅₇N₈O₆:841.44 Found m/z 841.50 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min and an analysis time of 5 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.33 (s,1H), 8.25 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 8.06 (d, J=8.7 Hz, 1H),7.97-7.85 (m, 8H), 5.82-5.75 (m, 2H), 4.31-4.28 (m, 2H), 3.73-3.71 (m,8H), 2.75-2.69 (m, 2H), 2.44-2.37 (m 2H), 2.17-2.12 (m, 2H), 1.40 (s,6H), 1.1-1.11 (m, 4H), 1.01-0.99 (m, 12H).

Methyl((1S)-2-((1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (62 mg, 0.164 mmol) was added to a stirred solution of the tetraHCl salt of(1S,3S,5S)-5-methyl-3-(4-(4-(6-(2-((1S,3S,5S)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (Intermediate 209) (50 mg, 0.074 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(35.5 mg, 0.164 mmol), and Hunig's base (0.104 mL, 0.595 mmol) in DMF (1mL). The reaction was stirred 1 h at room temperature and partiallyconcentrated by purge of nitrogen gas. The residue was taken up in MeOHand purified by preparative HPLC (MeCN/water with 0.1% TFA) to afford abis TFA salt of methyl((1S)-2-((1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(46.3 mg, 51%). LC-MS retention time 3.15 min; calcd. for C₅₂H₆₁N₈O₆:925.46 Found m/z 463.36 [M/2+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min and an analysis time of 5 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.31 (s,1H), 8.25 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H),7.97-7.85 (m, 8H), 5.80-5.74 (m, 2H), 4.36-4.35 (m, 2H), 3.99-3.95 (m,4H), 3.76-3.74 (m, 8H), 3.43-3.35 (m, 4H), 2.75-2.68 (m, 2H), 2.44-2.37(m 2H), 2.06-2.04 (m, 2H), 1.74 (app. d, J=13 Hz, 2H), 1.52-1.35 (m,12H), 1.22-1.19 (m, 2H), 1.14-1.12 (m, 2H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (31 mg, 0.082 mmol) was added to a stirred solution of the tetraHCl salt of(1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 211) (25 mg, 0.037 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14 mg, 0.082 mmol),and Hunig's base (0.052 mL, 0.297 mmol) in DMF (1 mL). The reaction wasstirred 1 h at room temperature and partially concentrated by purge ofnitrogen gas. The residue was taken up in MeOH and purified bypreparative HPLC (MeCN/water with 0.1% TFA) to afford a bis TFA salt ofMethyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(17 mg, 41%). LC-MS retention time 3.10 min; calcd. for C₄₈H₅₇N₈O₆:841.44 Found m/z 841.542 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min and an analysis time of 5 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.27 (s,1H), 8.26 (s, 1H), 8.12 (d, J=8.5 Hz, 1H), 8.07 (d, J=8.7 Hz, 1H),7.98-7.93 (m, 4H), 7.88-7.85 (m, 4H), 5.09-5.04 (m, 2H), 4.55-4.53 (m,2H), 3.38 (s, 6H), 3.57 (br.s, 2H), 2.81-2.75 (m, 2H), 2.33-2.27 (m 2H),2.22-2.16 (m, 2H), 1.44 (s, 3H), 1.43 (s, 3H), 1.05-0.93 (m, 16H).

Methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

HATU (34.8 mg, 0.092 mmol) was added to a stirred solution of the tetraHCl salt of(1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(Intermediate 211) (28 mg, 0.042 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (20mg, 0.092 mmol), and Hunig's base (0.085 mL, 0.333 mmol) in DMF (2 mL).The reaction was stirred 1 h at room temperature and partiallyconcentrated by purge of nitrogen gas. The residue was taken up in MeOHand purified by preparative HPLC (MeCN/water with 0.1% TFA) to afford abis TFA salt of methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate(13 mg, 25%). LC-MS retention time 2.92 min; calcd. for C₅₂H₆₁N₈O₆:925.46 Found m/z 92.53 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® C18 2.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min and an analysis time of 5 min whereSolvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5%water/0.1% TFA. MS data was determined using a MICROMASS® Platform forLC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.28 (s,2H), 8.14 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 8.00-7.96 (m, 4H),7.91-7.84 (m, 4H), 5.08-5.02 (m, 2H), 4.59-4.56 (m, 2H), 4.00-3.94 (m,4H), 3.69 (s, 6H), 3.62 (br. s, 2H), 3.44-3.38 (m, 4H), 2.81-2.78 (m,2H), 2.31-2.29 (m, 2H), 2.09 (br. s, 2H), 1.60-1.47 (m, 8H), 1.43 (s,3H), 1.44 (s, 3H), 1.04 (br. s, 2H), 0.98-0.97 (m, 2H).

Methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (97 mg, 0.254 mmol) was added to a stirred solution of the tetraHCl salt of2-((2S,4S)-4-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,4S)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole(Intermediate 196) (150 mg, 0.231 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (50mg, 0.231 mmol), and Hunig's base (0.162 mL, 0.925 mmol) in DMF (1 mL).The reaction was stirred 1 h at room temperature before addition of(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (40.5 mg, 0.231 mmol)and add′l Hunig's base (0.162 mL, 0.925 mmol) and HATU (97 mg, 0.254mmol). The mixture was stirred further at rt for 1 h and partiallyconcentrated by purge of nitrogen gas. The residue was taken up in MeOHand purified by preparative HPLC (MeCN/water with 0.1% TFA). A secondmethod of chromatography was applied to separate the isomers: SFCDiol-HL column, 20% methanol with 0.1% DEA; 4.6×250 mm, 5 μm MobilePhase: 80% CO₂-20% methanol with 0.1% DEA; Temp: 35° C.; Pressure: 150bar; Flow rate: 2 ml/min; UV monitored at 328 nm. The isolated samplewas taken up in methanol (3 mL) and neat TFA (50 mL) was added at rt.The mixture was concentrated down to dryness and placed on high vacuumto afford a bis TFA salt of methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(78.2 mg, 29.5% yield). LC-MS retention time 2.95 min; calcd. forC₄₈H₅₉N₈O₇: 859.45 Found m/z 859.50 [M+H]⁺. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C182.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% MeOH/95% water/0.1% TFAand Solvent B was 95% MeOH/5% water/0.1% TFA. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFAsalt, 500 MHz, MeOD) δ ppm 8.30 (s, 1H), 8.28 (s, 1H), 8.15 (d, J=8.6Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.01-7.85 (m, 8H), 5.26-5.22 (m, 2H),4.42-4.36 (m, 2H), 4.30-4.27 (m, 1H), 4.24-4.23 (m, 1H), 3.95-3.91 (m,2H), 3.68 (s, 6H), 3.47-3.36 (m 2H), 3.08-3.04 (m, 1H), 2.70 (br. s,2H), 2.55 (br. s, 2H), 2.08-2.03 (m, 1H), 1.97-1.87 (m, 3H), 1.59 (d,J=13.0 Hz, 1H), 1.48-1.26 (m, 10H) 0.95-0.90 (m, 6H).

Methyl((1S)-2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

The other isomer as reported in Example 140. LC-MS retention time 2.98min; calcd. for C₄₈H₅₉N₈O₇: 859.45 Found m/z 859.58 [M+H]⁺. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped aPHENOMENEX® Luna C18 2.0×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0%Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 minand an analysis time of 5 min where Solvent A was 5% MeOH/95% water/0.1%TFA and Solvent B was 95% MeOH/5% water/0.1% TFA. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFAsalt, 500 MHz, MeOD) δ ppm 8.29 (s, 1H), 8.28 (s, 1H), 8.13 (d, J=8.6Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.99-7.86 (m, 4H), 7.91-7.85 (m, 4H),5.26-5.21 (m, 2H), 4.41-4.36 (m, 4H), 4.28 (d, J=8.24 Hz, 1H), 4.24 (d,J=7.32 Hz, 1H), 3.95-3.91 (m, 2H), 3.68 (s, 6H), 3.47-3.36 (m 2H),2.73-2.66 (m, 2H), 2.59-2.53 (m, 2H), 2.07-2.03 (m, 1H), 1.97-1.87 (m,3H), 1.59 (d, J=13.0 Hz, 1H), 1.51-1.25 (m, 11H) 0.95-0.90 (m, 6H).

Methyl((1S)-1-(((2S,4S)-2-(4-chloro-5-(6-(4-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

The NCS (18.0 mg, 0.135 mmol) was added to a nitrogen purged solution ofExample 128 (55 mg, 0.067 mmol) in DMF (1 mL) and the reaction mixturewas stirred for 18 h at 50° C. The solvent was removed by concentrate,and the crude product was taken up in CH2Cl2 and charged to a 4 gThompson silica gel cartridge. Gradient elution was performed from5-100% B over 1 L. A/B (A=CH₂Cl₂; B=10% MeOH/EtOAc). A sample of thepurified product was taken up in MeOH and subject to preparative HPLC(MeCN/water with 0.1% TFA) to afford a bis TFA salt of methyl((1S)-1-(((2S,4S)-2-(4-chloro-5-(6-(4-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate. LC-MS retention time 4.48 min; calcd. for C₄₆H₅₅Cl₂N₈O₆:885.36 Found m/z 885.34 [M+H]⁺. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped a PHENOMENEX® Luna C18 2.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 0.8 mL/min, agradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B,a gradient time of 4 min, a hold time of 1 min and an analysis time of 5min where Solvent A was 5% MeOH/95% water/0.1% TFA and Solvent B was 95%MeOH/5% water/0.1% TFA. MS data was determined using a MICROMASS®Platform for LC in electrospray mode. ¹H NMR (TFA salt, 500 MHz, MeOD) δppm 8.20 (s, 1H), 8.18 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.6Hz, 1H), 7.90-7.83 (m, 6H), 5.09-5.04 (m, 2H), 4.30-4.7 (m, 2H),4.24-4.23 (m, 2H), 3.68 (s, 6H), 3.43-3.99 (m, 2H), 2.58-2.56 (m 2H),2.43 (br. s, 2H), 2.05-2.04 (m, 2H), 1.93-1.87 (m, 2H), 1.24-1.22 (m,6H), 0.97-0.91 (m, 12H).

Methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (34 mg, 0.090 mmol) was added to a stirred solution of an HCl saltof4-chloro-2-((2S,4S)-4-methylpyrrolidin-2-yl)-5-(6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazole(30.0 mg, 0.041 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (15.7 mg, 0.090 mmol), and Hunig's base (0.057 mL, 0.33 mmol) inDMF (1 mL). The reaction was stirred 1 h at room temperature andpartially concentrated by purge of nitrogen gas. The residue was takenup in MeOH and purified by preparative HPLC (MeCN/water with 0.1% TFA)to afford a TFA salt of methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(24.5 mg) as an off-white solid. LC-MS retention time 3.77 min; calcd.for C₄₆H₅₆C1N₈O₆: 851.40 Found m/z 851.42 [M+H]. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped a PHENOMENEX® C182.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% MeOH/95% water/0.1% TFAand Solvent B was 95% MeOH/5% water/0.1% TFA. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFAsalt, 500 MHz, MeOD) δ ppm 8.23 (s, 1H), 8.22 (s, 1H), 8.06 (d, J=8.9Hz, 1H), 8.02 (d, J=8.9 Hz, 1H), 7.98 (d, J=8.2 Hz, 2H), 7.93-7.89 (m,3H), 7.85 (d, J=8.9 Hz, 2H), 5.26-5.22 (m, 1H), 5.07-5.04 (m, 1H), 4.36(t, J=9.1 Hz 1H), 4.29-4.23 (m, 3H), 3.68 (s, 3H), 3.67 (s, 3H), 3.41(dt, J=10.7, 4.3 Hz, 2H), 2.72-2.67 (m, 1H), 2.58-2.53 (m 2H), 2.45-2.40(m, 1H), 2.06-2.02 (m, 2H), 1.91-1.83 (m, 2H), 1.26 (d, J=6.1 Hz, 3H),1.22 (d, J=8.9 Hz, 3H), 0.97-0.91 (m, 12H).

Methyl((1S)-2-((2S,4S)-2-(4-(4-(6-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

HATU (51 mg, 0.134 mmol) was added to a stirred solution of an HCl saltof4-chloro-2-((2S,4S)-4-methylpyrrolidin-2-yl)-5-(6-(4-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazole(32.7 mg, 0.061 mmol),(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(29.2 mg, 0.134 mmol), and Hunig's base (0.085 mL, 0.49 mmol) in DMF (1mL). The reaction was stirred 1 h at room temperature and partiallyconcentrated by purge of nitrogen gas. The residue was taken up in MeOHand purified by preparative HPLC (MeCN/water with 0.1% TFA) to afford aTFA salt of methyl((1S)-2-((2S,4S)-2-(4-(4-(6-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(22 mg) as a light yellow solid. LC-MS retention time 3.55 min; calcd.for C₅₀H₆₀ClN₈O₈: 935.42 Found m/z 935.52 [M+H]. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped a PHENOMENEX® C182.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% MeOH/95% water/0.1% TFAand Solvent B was 95% MeOH/5% water/0.1% TFA. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (TFAsalt, 500 MHz, MeOD) δ ppm 8.21 (s, 2H), 8.05 (d, J=8.9 Hz, 1H), 8.02(d, J=8.9 Hz, 1H), 7.92 (d, J=8.6 Hz, 2H), 7.93-7.89 (m, 3H), 7.85 (d,J=8.2 Hz, 2H), 5.25-5.22 (m, 1H), 5.06-5.02 (m, 1H), 4.40 (t, J=8.9 Hz1H), 4.31-4.27 (m, 3H), 3.95-3.92 (m, 4H), 3.68 (s, 3H), 3.67 (s, 3H),3.46-3.36 (m, 6H), 2.72-2.67 (m, 1H), 2.57-2.52 (m 2H), 2.45-2.40 (m,1H), 1.98-1.86 (m, 4H), 1.61-1.59 (m, 2H), 1.56-131. (m, 6H), 1.27 (d,J=6.4 Hz, 3H), 1.22 (d, J=6.4 Hz, 3H).

Methyl((1S)-1-(((2S,4S)-2-(4-(6-(4-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

NCS (108 mg, 0.808 mmol) was added to a solution of a TFA salt of methyl((1S)-1-(((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(550 mg, 1.385 mmol) in dry DMF (10 mL) and the mixture was heated at50° C. for 18 h. The solvent was removed by rotary evaporation underhigh vacuum and the residue was purified utilizing a Thompson 25 gsilica gel cartridge (gradient elution 5%-100% B over 1 L; Solvent B=10%MeOH in ethyl acetate and Solvent A=dichloromethane). The partiallypurified product was subjected to prep HPLC (CH₃CN/H₂O/TFA) on aWaters-Sunfire column (30×100 mm S5) 0-80% B over 35 min and the monochloro adducts (116 mg, 20% as a 7:1 mixture favoring Example 145) wereseparated from dichloro adduct (see Example 142). The mono chloroadducts were further purified by chiral SFC chromatography; CHIRALCEL®OJ-H column (85% CO₂; 15% EtOH with 0.1% DEA) to yield methyl((1S)-1-(((2S,4S)-2-(4-(6-(4-(4-chloro-2-((2S,4S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(10 mg) as a yellowish residue. LC-MS retention time 3.75 min; calcd.for C₄₆H₅₆C1N₈O₆: 851.40 Found m/z 851.39 [M+H]. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 0.8mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B, a gradient time of 4 min, a hold time of 1 min and ananalysis time of 5 min where Solvent A was 5% methanol/95% water/0.1%TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data wasdetermined using a MICROMASS® Platform for LC in electrospray mode. ¹HNMR (TFA salt, 500 MHz, MeOD) δ ppm 8.20 (s, 1H), 8.15 (s, 1H), 8.01 (d,J=8.2 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.86 (d,J=7.0 Hz, 1H), 7.83 (d, J=7.3 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.44 (s,1H), 5.14-5.10 (m, 1H), 5.06-5.02 (m, 1H), 4.27-4.22 (m, 4H), 3.67 (s,6H), 3.46-3.47 (m, 2H), 2.57-2.51 (m, 2H), 2.45-2.39 (m 2H), 2.06-2.01(m, 2H), 1.95-1.90 (m, 2H), 1.23-1.22 (m, 6H), 0.97-0.91 (m, 12H).

Methyl(2-((2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(((methoxycarbonyl)amino)(tetrahydro-2H-pyran-4-yl)acetyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

Example 146 (22 mg, 13%) was obtained and isolated from the samereaction that produced Example 129 and as a diastereomer thereof. LC-MSretention time 2.86 min; calcd. for C₅₀H₆₁N₈O₈: 901.46 Found m/z 901.42[M+H]. LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped a PHENOMENEX® C18 2.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, ahold time of 1 min and an analysis time of 5 min where Solvent A was 5%MeOH/95% water/0.1% TFA and Solvent B was 95% MeOH/5% water/0.1% TFA. MSdata was determined using a MICROMASS® Platform for LC in electrospraymode. ¹H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.34/8.29 (s, 1H), 8.27 (s,1H), 8.13 (d, J=7.63 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.99-7.95 (m, 4H),7.92-7.87 (m, 4H), 5.29-5.21 (m, 2H), 4.38 (t, J=7.3 Hz, 1H), 4.31-4.28(m, 2H), 4.16-4.13 (m, 1H), 3.99-3.91 (m, 4H), 3.68 (s, 3H), 3.65/3.61(s, 3H), 3.56-3.36 (m, 6H), 2.76-2.62 (m, 2H), 2.56 (br. s, 2H),2.00-1.83 (m, 4H), 1.71 (d, J=12.8 Hz, 1H), 1.31-131 (m, 7H), 1.26-1.2(m, 6H).

Methyl((1S)-2-((5S)-5-(4-(4-(6-(2-((3S)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-1-methyl-3-pyrazolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-methyl-1-pyrazolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

(S)-tert-Butyl5-(4-(4-(6-(2-((S)-2-(tert-butoxycarbonyl)-1-methylpyrazolidin-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-methylpyrazolidine-1-carboxylate(48.4 mg, 0.069 mmol) was dissolved into dioxane (1.2 mL) and then 4MHCl (0.687 mL, 2.75 mmol) in dioxane was added and the resulting slurrywas stirred for 4 h. The reaction was concentrated and the residue and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(37.3 mg, 0.172 mmol) were dissolved into DMF (1.0 mL) and DIPEA (0.072mL, 0.41 mmol). The reaction mixture was treated with HATU (65 mg, 0.17mmol) and the reaction was stirred at rt for 1 h. The reaction wasconcentrated to dryness with a stream of nitrogen, dissolved into MeOH,filtered and purified by prep HPLC (MeOH/water with TFA buffer) to yieldmethyl((1S)-2-((5S)-5-(4-(4-(6-(2-((3S)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-1-methyl-3-pyrazolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-methyl-1-pyrazolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(9.2 mg) as a yellow solid. LC-MS retention time 3.261 min; m/z 903.36(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 3 u C18 2.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 0.8 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min whereSolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and Solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a MICROMASS® Platform for LC in electrospray mode. ¹H NMR (400MHz, MeOD) δ ppm 8.32 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.5 Hz, 1H),8.09 (d, J=8.8 Hz, 1H), 7.94-8.00 (m, 4H), 7.85-7.93 (m, 4H), 5.47 (q,J=8.1 Hz, 2H), 3.93-4.01 (m, 4H), 3.66 (s, 6H), 3.34-3.49 (m, 6H),3.20-3.34 (m, 4H), 2.77 (s, 3H), 2.77 (s, 3H), 2.65-2.96 (m, 4H), 2.08(br. s., 2H), 1.38-1.73 (m, 8H).

Methyl((1R)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)amino)-2,2-dimethylpropyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)carbamoyl)-2-methylpropyl)carbamate

To a mixture of an HCl salt of(S)-1-(5-(4-(6-(2-((S)-1-amino-2,2-dimethylpropyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine(0.04 g, 0.061 mmol), (R)-2-(methoxycarbonylamino)-3-methylbutanoic acid(0.021 g, 0.123 mmol) and HATU (0.051 g, 0.135 mmol) in DMF was addedDIPEA (0.064 mL, 0.368 mmol). The reaction mixture was stirred at rt for1 h. The reaction mixture was purified by reverse phase HPLC to yield aTFA salt of methyl41R)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)amino)-2,2-dimethylpropyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)carbamoyl)-2-methylpropyl)carbamate(0.020 g) as a white solid. LC-MS (Cond. 1; shown below): [M+H]⁺ 821.55,R_(t)=3.316 min; ¹H NMR (400 MHz, MeOD) ppm 8.34 (1H, s), 8.27 (1H, d,J=1.25 Hz), 8.11 (2H, dd, J=15.94, 8.91 Hz), 7.84-8.02 (8H, m), 4.94(2H, s), 4.07 (2H, dd, J=7.78, 3.76 Hz), 3.60 (6H, d, J=9.29 Hz),1.94-2.14 (2H, m), 1.16 (18H, d, J=5.27 Hz), 0.95-1.07 (12H, m). Cond.1: Column=PHENOMENEX®, 2.0×50 mm, 3 μm; Start % B=0; Final % B=100;Gradient time=4 min; Stop time=5 min; Flow Rate=0.8 mL/min;Wavelength=220 nm; Solvent A=0.1% TFA in 10% methanol/90% water; SolventB=0.1% TFA in 90% methanol/10% water; Oven temp.=40° C.)

Example 149 and Example 150

Example 149 (a TFA salt of methyl((1S)-1-(((1S)-1-(4-(4-(6-(2-((1S)-1-(((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)amino)-2,2-dimethylpropyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)carbamoyl)-2-methylpropyl)carbamate)and Example 150 (a TFA salt ofN-((1S)-1-(4-(4-(6-(2-((1S)-2,2-dimethyl-1-((3-methylbutanoyl)amino)propyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)-3-methylbutanamide)were prepared from2-bromo-1-(4-(6-(2-bromoacetyl)naphthalen-2-yl)phenyl)ethanone and theappropriate starting materials, obtained from commercial sources, byemploying the procedures described for the synthesis of Example 148.Cond. 2: Column=Sunfire, C18, 3.0×150 mm, 3.5 μm; Start % B=0; Final %B=100; Gradient time=15 min; Stop time=18 min; Flow Rate=1 mL/min;Wavelength 1=220 nm; Wavelength 2=254 nm; Solvent A=0.1% TFA in 5%MeCN/95% water; Solvent B=0.1% TFA in 95% MeCN/5% water

Example R Analytical conditions 149

LC (Cond. 2): >95% homogeneity index. LC-MS (Cond. 1): [M + H]⁺ 821.55,R_(t) = 3.348 min. 150

LC (Cond. 2): >95% homogeneity index. LC-MS (Cond. 1): [M + H]⁺ 675.51,R_(t) = 3.488 min.

Example 154

In a 500-mL reactor Example 151 (commercially available, 17.5 g, 1.00equiv) was dissolved in THF (87.5 mL). The resulting solution was cooledto −75° C. and 1.5M DIBAL-H in toluene (61.3 mL, 1.5 equiv) was chargedwhile maintaining the temperature below −70° C. The resulting solutionwas stirred at −70° C. for 1 hour. Trifluoroacetic acid (2.3 mL, 0.5equiv) was charged over 10 minutes maintaining the internal temperaturebelow −70° C. Triethylamine (51.3 mL, 6 equiv) was then charged over 15minutes maintaining the internal temperature below −70° C.Trifluoroacetic anhydride (11.2 mL, 1.3 equiv) was charged over 10minutes maintaining the internal temperature below −70° C. The reactionwas then allowed to warm to room temperature over 90 minutes andquenched via inverse addition to a solution of 20 wt % aqueous citricacid monohydrate (96.6 g, 1.5 equiv) while maintaining a temperaturebelow 15° C. The resulting mixture was stirred at room temperature for 2hours then the lower aqueous layer was discarded. The product richorganic layer was washed twice with 70 mL saturated aqueous sodiumbicarbonate. Solid sodium bicarbonate (1.7 g, 0.1 g/g Example 146) wascharged and the solution was solvent exchanged into pure toluene undervacuum to provide Example 152 as a solution in 2 L/kg toluene.

A solution of Example 152 (16.5 g theoretical from Example 151) in 33 mLtoluene was polish filtered into a 250 mL reactor. Trifluorotoluene (50mL) and chloroiodomethane (43.2 g, 4.0 equiv) were then charged and theresulting solution cooled to −20° C. 1.1M Diethylzinc in toluene (111mL, 2.0 equiv) was charged while maintaining the internal temperature<−8° C. The resulting solution was stirred at −15 to −20° C. for 14hours. The reaction mixture was warmed to 0° C. then quenched viainverse addition to a solution of 20 wt % aqueous citric acid (135.7 g,2.3 equiv). The reactor was rinsed with toluene (82 mL) and the rinseadded to the quench solution. The resulting biphasic mixture was stirredfor 20 minutes then the lower aqueous layer was split and discarded. Therich organic was washed twice with 60 mL 13 wt % aqueous NaCl followedby 60 mL saturated NaHCO₃. The resulting solution was solvent exchangedinto pure IPA under vacuum to provide Example 153 as a solution in 10L/kg IPA.

A 250 mL reactor was charged with a solution of Example 153 (147 mL,14.7 g theoretical from Example 151) in IPA. The solution was warmed to35° C. and solid sodium hydroxide (6.2 g, 3.0 equiv) was added. Theresulting mixture was stirred at 35° C. overnight. Water (44 mL) wasadded and the organic solvents removed under vacuum. MTBE (145 ml) wasadded and the pH adjusted to 3.0 with 6N aqueous HCl. The aqueous layerwas split and discarded. The product rich organic was washed with 60 mLwater then azeotropically dried under vacuum via constant volumeaddition of MTBE. The solution was concentrated to 55 mL and stirred at50° C. for 30 minutes. The solution was cooled to room temperature over1 hour during which time a slurry formed. Heptane (90 mL) was chargedover 90 min and the resulting slurry aged for 1 h. The solids werecollected on a medium glass frit and washed with 22.5 mL 3:1heptane:MTBE followed by 22.5 mL heptane. The tan solid was dried in a50° C. vacuum oven to provide 5.48 g (46%) Example 154 with 94.9 LCAPpurity.

The crude Example 154 was dissolved in 55 mL MTBE at 50° C. Theresulting solution was concentrated to 20 mL and cooled to roomtemperature over 1 hour. Heptane (33 mL) was then added over 90 minutes.The resulting solids were collected on a medium glass frit, washed withheptane (15 mL), and dried in a 50° C. vacuum oven to provide 4.45 g(98.8 AP, 98.8% chiral purity, 37% from Example 151) of the desiredproduct as a tan powder.

It is expected that the above reaction sequence (for the formation ofExample 154) would be general enough to tolerate other functionality aswell. For example, the tert-butoxycarbonyl group on the C2 carbon ofExample 147 could potentially be replaced with an amide or anotherester. Likewise, the tert-butoxycarbonyl protecting group on thenitrogen could be replaced by other protecting groups (such as othercarbamates, amides, alkyl, aryl) or could be absent entirely (replacedwith a hydrogen).

BIOLOGICAL ACTIVITY

An HCV Replicon assay was utilized in the present disclosure, and wasprepared, conducted and validated as described in commonly ownedPCT/US2006/022197 and in O'Boyle et al., Antimicrob. Agents Chemother.,49(4):1346-1353 (April 2005). Assay methods incorporating luciferasereporters have also been used as described (Apath.com).

HCV-neo replicon cells and replicon cells containing resistancesubstitutions in the NS5A region were used to test the currentlydescribed family of compounds. The compounds were determined to havediffering degrees of reduced inhibitory activity on cells containingmutations vs. the corresponding inhibitory potency against wild-typecells. Thus, the compounds of the present disclosure can be effective ininhibiting the function of the HCV NS5A protein and are understood to beas effective in combinations as previously described in applicationPCT/US2006/022197 and commonly owned WO 04/014852. It should beunderstood that the compounds of the present disclosure can inhibitmultiple genotypes of HCV. Table 2 shows the EC₅₀ (Effective 50%inhibitory concentration) values of representative compounds of thepresent disclosure against the HCV 1b genotype. In one embodiment,compounds of the present disclosure are inhibitory versus 1a, 1b, 2a,2b, 3a, 4a, and 5a genotypes. EC₅₀ values against HCV 1b are as follows:A=0.4 pM-10 pM; B=10.1 pM-1.00 nM; and C=1.01 nM-1 μM.

The compounds of the present disclosure may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present disclosure inhibit HCV replicon and in anotherembodiment the compounds of the present disclosure inhibit NS5A.

TABLE 2 Example Number (unless noted otherwise) EC50 (μM) RangeIntermediate 52  C Intermediate 70  C Intermediate 114 C  1 C  22.18E−06 A  3 B  4 C  5 B  6 A  7 B  8 B  9 A 10 A 11 1.82E−05 B 12 C 13C 14 C 15 B 16 A 17 C 18 A 19 B 20 A 21 A 22 B 23 8.88E−04 B 24 B   25AC   25B C 26 B 27 4.77E−06 A 28 B 29 A 30 A 31 B 32 B 33 A 34 A 35 A 36A 37 A 38 4.21E−05 B 39 B 40 A 41 A 42 B 43 A 44 A 45 B 46 0.17 C 47 A48 B 49 A 50 B 51 B 52 5.90E−06 A 53 1.81E−03 C 54 A 55 A 56 A 57 A 588.49E−04 B 59 A 60 A 61 A 62 A 63 A 64 A 65 9.97E−07 A 66 A 67 A 68 A 69A 70 A 71 2.11E−06 A 72 A 73 A 74 75 1.23E−04 C 76 77 A 78 A 79 A 801.08E−06 A 81 A 82 4.22E−05 B 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91A 92 A 93 0.04 C 94 A 95 A 96 B 97 A 98 B 99 A 100  A 101  A 102  A 103 A 104  2.01E−06 A 105  A 106  A 107  A 108  109  0.18 C 110  A 111  A112  A 113  114  B 115  A 116  B 117  118  3.74E−05 B 119  A 120  A 121 A 122  A 123  A 124  B 125  1.36E−04 B 126  6.54E−04 B 127  A 128  A129  B 130  A 131  — 132  A 133  A 134  A 135  B 136  A 137  A 138  A139  A 140  A 141  A 142  A 143  1.05E−06 A 144  1.77E−05 B 145  A 146 A 147  A 148  8.43E−03 C 149  B 150  C

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

What is claimed is:
 1. A compound which is

or a pharmaceutically acceptable salt thereof.